A  TEXT-BOOK   OF   ORGANIC   CHEMISTRY 


- 


THE  MACMILLAN  COMPANY 

NEW  YORK    •    BOSTON   •    CHICAGO  «    DALLAS 
ATLANTA  •   SAN  FRANCISCO 

MACMILLAN  &   CO.,  LIMITED 

LONDON  '    BOMBAY  •    CALCUTTA 
MELBOURNE 

THE  MACMILLAN  CO.  OF  CANADA,  LTD. 

TORONTO 


A  TEXT-BOOK 

OF 

ORGANIC   CHEMISTRY 

FOE  STUDENTS  OF  MEDICINE  AND  BIOLOGY 


BY 
E.    V.    McCOLLUM,   PH.D. 

PROFESSOR     OF     BIOCHEMISTRY,     SCHOOL     OF     HYGIENE,     JOHNS     HOPKINS 

MEDICAL    SCHOOL  J    FORMERLY    PROFESSOR    OF    AGRICULTURAL 

CHEMISTRY.    UNIVERSITY    OF   WISCONSIN 


THE   MACMILLAN   COMPANY 
1917 

All  rights  reserved 


COPYRIGHT,  1916, 
BY  THE  MACMILLAN  COMPANY. 


Set  up  and  electrotyped.     Published  October,  1916.     Reprinted 
July,  1917. 


J.  S.  Gushing  Co.  —Berwick  &  Smith  Co. 
Norwood,  Mass.,  U.S.A. 


PREFACE 

IN  preparing  this  text-book  the  aim  has  been  to  re- 
strict its  contents  to  a  degree  which  should  make  it 
suitable  for  a  course  continuing  through  a  half  of  an 
academic  year.  The  book  embodies  the  substance  of 
the  discussion  of  organic  chemistry  presented  with  the 
author's  course  in  the  chemistry  of  nutrition  during 
the  last  eight  years,  and  emphasizes  the  biological 
rather  than  the  synthetic  and  technical  viewpoint.  It 
is  hoped,  therefore,  that  it  should  serve  as  a  satisfactory 
text  for  students  of  medicine  and  others  who  can  give 
but  a  semester  to  this  subject,  and  whose  interest  is  in 
some  field  of  biology. 

The  text-books  ordinarily  placed  in  the  hands  of  stu- 
dents contain  more  matter  than  can  be  assimilated  in 
an  academic  year,  and  make  necessary  some  omissions. 
They  reflect  the  special  interests  of  their  writers  in 
extending  the  subject  matter  relating  to  methods  of 
synthesis,  with  an  undesirable  multiplication  of  indi- 
vidual compounds  described,  or  in  restricting  these  and 
extending  the  description  of  technical  processes.  It 
has  not  infrequently  been  the  case  that  in  text-books 
designed  for  medical  students  the  other  extreme  has 
been  reached,  and  wholly  inadequate  evidence  has 
been  offered  in  support  of  the  structural  formulas  pre- 
sented. The  book  then  consists  of  a  description  of 


*>  I*  /*  "V  "' 

ebb  7-5 


VI 


Preface 


the  biologically  important  compounds,  burdened  with 
formidable  formulas  in  which  the  student  sees  no 
meaning. 

It  is  the  belief  of  the  author  that,  if  properly  pre- 
sented, the  theory  of  organic  chemistry  never  fails  to 
arouse  the  interest  of  a  bright-minded  student.  To  be 
appreciated  by  the  beginner  it  must  be  shorn  as  far 
as  possible  of  details  which  burden  the  memory.  The 
aim  has  been  to  present  a  complete  line  of  reasoning, 
based  upon  the  properties  of  the  substances  considered, 
in  support  of  the  validity  of  every  formula  employed. 
This  end  has  been  attained  except  in  the  case  of  the 
terpenes  and  a  few  alkaloids.  In  all  cases  the  effort 
has  been  made  to  select  for  purposes  of  illustration 
those  compounds  which  have  biological  importance 
rather  than  technical.  The  course  here  offered  will, 
it  is  hoped,  serve  to  fit  the  student  for  intelligent  work 
in  physiological  chemistry  by  giving  him  an  apprecia- 
tion of  the  spirit  of  organic  chemistry  and  an  under- 
standing of  the  relationships  and  transformations  which 
go  on  in  the  plant  and  animal  world. 

Since  the  book  is  not  intended  to  serve  as  a  guide 
to  manipulation  the  usual  introductory  chapter  on 
methods  of  laboratory  work  is  omitted.  Such  infor- 
mation is  now  readily  available  in  a  number  of  labora- 
tory manuals. 

E.  V.  McCOLLUM. 


TABLE   OF   CONTENTS 


CHAPTER  I 

THE  SATURATED  FATTY  HYDROCARBONS  (1-11)  .         .        .          1-22 

Methane,  1.  Derivatives  of  methane,  3.  Structure 
of  methane,  6.  Chlor  derivatives,  7.  Methyl  iodide, 
10.  Ethane,  10.  Nomenclature  of  the  hydrocarbons, 
14.  Petroleum,  15.  Isomerism  of  the  hydrocarbons,  17. 

CHAPTER  II 

THE  ALCOHOLS  (12-27) 23-43 

Nomenclature  of  the  alcohols,  23.  Ethyl  alcohol,  24. 
Alcoholates,  26.  Alcoholic  beverages,  27.  Homologues 
of  ethyl  alcohol,  28.  Propyl,  butyl,  and  amyl  alcohols, 
28.  Isomerism  of  the  amyl  alcohols,  31.  Higher  alco- 
hols, 36.  Diatomic  alcohols,  37.  Triatomic  alcohols,  39. 
Tetratomic  alcohols,  42.  Mercaptans,  42. 

CHAPTER  III 

ETHERS  AND  ESTERS  (28-29) 44-55 

Ethyl  sulphuric  acid,  44.  Esters  of  sulphurous  acid, 
46.  Ethers  of  sulphurous  acid,  47.  Ethyl  nitrate  and 
ethyl  nitrite,  48.  Amyl  nitrite,  48.  Structure  of  the 
ethers,  51.  Methyl  and  ethyl  ether,  50.  Mixed  ethers,  52. 

CHAPTER   IV 

ALDEHYDES  AND  KETONES  (30-39) 56-76 

Constitution  of  aldehydes  and  acids,  56.     Properties 
of  the  aldehydes.   57.     Formaldehyde,  63.     Acetalde- 
vii 


viii  Table  of  Contents 


hyde,  65.  Chloral,  66.  Glycol  aldehyde,  67.  Glycer- 
aldehyde,  68.  Ke tones,  68.  Methods  of  formation  and 
structure,  69.  Properties,  70.  Acetone,  73.  Dihydroxy 
acetone,  75. 

CHAPTER  V 

THE     NlTRILES     AND     THEIR     REDUCTION     PRODUCTS.         THE 

AMINES  (40-49) 77-95 

Structure  of  the  nitriles  and  isonitriles  as  shown  by 
their  modes  of  formation  and  chemical  behavior,  77. 
Cyanamide,  83.  Primary,  secondary,  and  tertiary 
amines,  84.  Methods  of  preparation  of  amines,  86. 
Isomerism  of  the  amines,  89.  Methyl  amine,  90. 
Ethyl  amine,  91.  Choline,  92.  Physiological  proper- 
ties of  the  amines,  94. 

CHAPTER   VI 

THE  FATTY  ACIDS  (50-77) 96-152 

Formic  acid,  96.  Acetic  acid,  99.  Acid  chlorides, 
103.  Acid  amides,  104.  Chlor  acetic  acids,  107.  Hy- 
droxy  acids,  108.  Amino  acids,  109.  Urea,  111.  Thio- 
urea,  115.  Esters  of  carbamic  acids,  116.  Urethanes, 
117.  Guanidine,  117.  Arginine,  118.  Glycocoll,  120.' 
Creatine  and  creatinine,  123.  Sarcosine,  124.  Betaines, 
125.  Acid  anhydrides,  126.  Propionic  acid,  and  its 
derivatives,  lactic  and  pyruvic  acids,  cystine  and  ala- 
nine,  127.  Stereochemistry  of  the  lactic  acids,  131. 
Butyric  acids,  140.  Valerianic  acid  and  valine,  142. 
The  caproic  acids  and  their  derivatives,  lysine,  leucine, 
and  isoleucine,  146.  The  higher  fatty  acids,  149. 

CHAPTER   VII 
THE  OLEFINES  AND  ACETYLENES  (78-88)     ....     153-174 

Methylene,  153.  Ethylene,  154.  Propylene,  169. 
Propylidene,  160.  Diolefines,  161.  Acetylene,  162. 
Substitution  products  of  the  unsaturated  hydrocarbons, 


Table  of  Contents 


IX 


167.  Allyl  alcohol,  167.  Acrolein,  168.  Acids  of  the 
oleic  acid  series,  acrylic,  and  crotonic,  169.  Oleic  acid, 
172.  Acids  with  two  and  three  double  bonds,  173. 


CHAPTER   VIII 

THE  FATS  AND  WAXES  AND  RELATED  COMPOUNDS  (89-99) 
The  animal  fats,  175.  The  vegetable  fats,  176.  Soaps, 
179.  The  cleansing  action  of  soaps,  181.  Methods  of 
characterization  of  the  fats,  183.  Waxes,  190.  Leci- 
thins and  phosphatides,  193.  Neurine,  195.  Cerebro- 
sides,  197.  Sterols,  197. 


175-198 


CHAPTER   IX 

THE  DIBASIC  ACIDS  (100-108) 199-209 

Oxalic  acid,  199.  Malonic  acid,  202.  Succinic  acid, 
205.  Aspartic  acid  and  asparagine,  206.  Glutaric  acid 
and  its  derivatives,  glutamic  acid  and  glutamine,  207. 
Adipic,  pimelic,  and  suberic  acids,  208. 

CHAPTER   X 
CYCLO  PARAFFINS  AND  PYRROLE  DERIVATIVES  (109-120)  .     210-224 

Trimethylene,  tetramethylene,  pentamethylene,  hexa- 
methylene,  and  heptamethylene,  210.  Anhydrides  of 
the  dibasic  axids,  215.  Succinimide  and  glutarimide, 
216.  Pyrrole  and  pyrrolidine,  216.  Proline,  223.  Oxy- 
proline,  224.  Pyrrolidone  carboxylic  acid,  224. 


CHAPTER   XI 

HYDROXY  AND  KETONE  ACIDS  (121-132)  .... 
Tartronic,  malic,  and  tartaric  acids,  225.  Oxybutyric 
acid,  235.  7-hydroxy  acids,  236.  7-amino  acids,  237. 
Acetoacetic  acid,  237.  Mesoxalic  acid,  242.  .Levulinic 
acid,  243.  Oxalacetic  acid,  243.  Acetone  dicarboxylic 
acid,  244.  Citric  acid,  245. 


225-246 


Table  of  Contents 


CHAPTER   XII 

MALEIC  AND  FUMARIC  ACIDS  AND  THEIR  ISOMERISM  (133) 
The  isomerism  due  to  the  double  bond,  247.    Trans- 
formation of  the  malenoid  into  the  fumaroid  form  and 
the  reverse  transformation,  251.    The  biological  proper- 
ties of  the  cis  and  trans  isomers,  252. 


PA.QE8 

247-262 


CHAPTER   XIII 

THE  UREIDES  (134-140)        .         .         .        .... 

Acetyl  urea,  253.  Diacetyl  urea,  253.  Glycoluric 
acid,  254.  Hydantoin,  255.  Allantoin,  256.  Histidine 
and  urocanic  acid,  257.  Pyrazole,  259.  Oxaluric  and 
parabanic  acids,  259.  Alloxan,  262. 


253-263 


CHAPTER  XIV 

THE  PYRIMIDINES,  PTRAZINES,  AND  PURINES  (141-149) 

Pyrimidines,  264.  Thymine,  265.  Cytosine,  265. 
Uracil,  266.  Pyrazines,  266.  Piperazine,  269.  Diketo 
piperazines,  270.  The  purines,  270.  Uric  acid,  271. 
Purine,  275.  Hypoxanthine  and  xanthine,  277.  Ade- 
nine  and  guanine,  278.  The  nucleic  acids,  280.  Methyl 
purines  —  theobromine  and  caffeine,  281. 


264-282 


CHAPTER  XV 

THE  CARBOHYDRATES  (150-163) 

Composition,  283.  Determination  of  structure,  285. 
Synthesis  of  carbohydrates,  288.  Determination  of  con- 
figuration, 297.  Pentoses,  301.  Methyl  pentoses,  303. 
Structure  of  the  hexoses,  303.  Ketoses,  307.  Special 
properties  of  the  hexoses,  311.  Action  of  alkalies  on 
glucose,  314.  Disaccharides,  318.  Importance  of  stereo- 
chemistry in  relation  to  the  biological  values  of  the 
sugars,  321.  Raffinose,  323.  Glucosides,  323.  Polysac- 
charides,  329.  Chitin  and  glucosamine,  334.  Inulin,  336. 


283-337 


Table  of  Contents 


XI 


CHAPTER  XVI 

PAGES 

THE  CHEMICAL  CHANGES  INVOLVED  IN  THE  FERMENTATION 

OF  THE  SUGARS  (164-165) 338-346 

Alcoholic  fermentation,  338.  Lactic  acid  fermenta- 
tion, 342.  Butyric  acid  fermentation,  342.  The  rela- 
tion of  the  intermediary  products  of  fermentation  to  the 
formation  of  fats  in  the  animal  body,  343. 


CHAPTER  XVII 

BENZENE  AND  ITS  DERIVATIVES  (166-214)  .... 
Structure  of  benzene,  347.  Determination  of  the 
position  of  substituting  groups,  350.  Physiological 
properties  of  benzene,  353.  Homologues,  353.  Tolu- 
ene, 353.  Structure  of  the  chlor  derivatives  of  toluene, 
355.  The  xylenes,  356.  Mesitylene,  356.  Halogen  de- 
rivatives of  benzene,  358.  Nitrobenzene,  369.  Aniline, 
359.  Acetanilide,  361.  Alkyl  anilines,  361.  Diphenyl 
amine,  361.  Diazobenzene,  362.  Benzene  sulphonic 
acid,  364.  Phenol,  365.  Phenol  sulphuric  acid,  366. 
Phenol  sulphonic  acid,  366.  Phenol  ethers,  367.  Cre- 
sols,  367.  Picric  acid,  368.  Tyrosine,  368..  Tyramine, 

370.  Dihydroxy  benzenes,  371.    Guiacol  and  veratrol, 

371.  Quinone,  372.     Trihydroxy  benzenes,  373.     Ino- 
site,  373.     Thymol  and  carvacrol,  374.     Protocatechuic 
acid,  374.     Veratric  acid,  vanillin,  and  coniferyl  alcohol, 
374.     Homogentisic  acid,  375.     Adrenin,  376.     Benzoic 
acid,  377.    Saccharin,  378.    Hippuric  acid,  378.    Benzyl 
alcohol,  379.     Benzaldehyde,  379.     Phenyl  acetic  acid 
and  phenyl  alanine,  380.    Cinnamic  acid,  381 .    Salicylic 
aldehyde  and  salicylic  acid,  381.     Aspirin,  381.     Salol, 
382.     Gallic  and  tannic  acids,  382.    Tannins,  382. 


347-383 


CHAPTER   XVIII 

CONDENSED  BENZENE  RINGS  (215-216) 

Naphthalene,  384.     Anthracene,  385. 


,     384-386 


Xll 


Table  of  Contents 


CHAPTER   XIX 

THE  DYES  (217-219) 

Alizerin,  387.     Triphenyl  methane  dyes,  388.    The 
azo  dyes,  390. 


387-390 


CHAPTER  XX 

HETEROCYCLIC  COMPOUNDS  (220-227)  .... 

Pyridine,  391.  Picolines,  393.  Nicotinic  acid,  393. 
Quinolinic  acid,  394.  Quinoline,  394.  Indole  and  its 
derivatives,  indole,  scatole,  indoxyl,  and  indigo,  395. 
Tryptophane,  398.  Transformation  products  of  tryp- 
tophane,  399. 


391-399 


CHAPTER  XXI 

THE  TERPENES  (228-229) 400-405 

Addition  products  of  the  terpenes  with  nitrosyl  chlo- 
ride and  ozone,  400.  Citronellol,  geraniol,  linalool,  and 
myrcene,  402.  Cymene,  menthene,  and  menthane,  403. 
Pineiie,  borneol,  and  camphor,  403.  The  cholesterols,  404. 


CHAPTER   XXII 

THE  ALKALOIDS  (230-239)    .... 

Piperine,  406.  Coniine,  406.  Nicotine,  407.  Hygrine, 
408.  Atropine  and  hyoscyamine,  408.  Cocaine,  409. 
Cinchonine,  410.  Strychnine,  410.  Morphine,  410.  Pa- 
paverine,  410.  Narcotine,  narceine,  and  laudanosine,  410. 


406-410 


CHAPTER   XXIII 

ORGANIC  ARSENIC  COMPOUNDS  (240-242)     .... 
Cacodylic  acid  and  cacodyl  oxide,  411.    Arrhenal,  412. 
Atoxyl,  412.     Salvarsan,  413.     Arsenobenzene,  414. 


411-413 


Table  of  Contents  xiii 

CHAPTER   XXIV 

PAGES 

THE  PROTEINS  (243) .         .    414-416 

The  physical  properties  of  the  proteins,  414.  Nature 
of  the  "  peptide "  union,  415.  Di-,  tri-,  tetra-,  etc., 
peptides,  415.  Yields  of  individual  amino  acids  by 
various  proteins,  416.  The  conjugated  proteins,  416. 


OKGANIC  CHEMISTRY  FOE  STUDENTS 
OF  MEDICINE 

THE  FATTY   COMPOUNDS 

CHAPTER   I 
THE  SATURATED  HYDROCARBONS 

1.  The  simplest  of  the  compounds  composed  of  carbon 
and  hydrogen  is  methane,  CH4.  The  compounds  con- 
taining only  these  two  elements  are  called  hydrocarbons. 
It  occurs  widely  distributed  in  nature,  in  the  gases  evolved 
from  volcanoes,  and  in  those  which  escape  from  coal 
mines,  where  it  is  called  fire  damp,  and  as  the  principal 
constituent  of  natural  gas.  Coal  gas  contains  consider- 
able amounts  of  this  compound  (30-40%),  since  it  results 
from  the  destructive  distillation  of  many  kinds  of  or- 
ganic matter.  Methane  also  results  from  the  degradation 
of  vegetable  matter,  especially  cellulose,  by  certain  kinds 
of  microorganisms.  In  this  way  it  is  produced  by  the 
fermentation  of  vegetable  tissues  under  water  in  marshes, 
and  derived  its  older  name  of  marsh  gas  in  this  way.  It 
is  an  ever  present  constituent  of  the  gases  in  the  intestines 
and  is  normally  found  in  small  amounts  in  the  respired 
air,  some  of  the  methane  produced  by  fermentation  in 
the  intestines  being  absorbed  into  the  circulation  and 
eliminated  through  the  lungs. 


. 


2     Organic  Chemistry  for  Students  of  Medicine 

Preparation : 

(a)  When  a  mixture  of  carbon  monoxide  and  hydrogen 
is  passed  through  a  tube  containing  reduced  nickel,  heated 
to  200°  C.,  there  is  produced  methane  and  water : 

CO  +'3  H2  =  CH4  +  H2O 

(6)  At  somewhat  higher  temperatures  (230°-300°  C.) 
carbon  dioxide  is  likewise  reduced  by  hydrogen  in  the 
presence  of  finely  divided  nickel,  the  latter  undergoing 
no  change:  CQ,  +  4  H2  =  CH,  +  2  H2O 

(c)  Hydrogen  sulphide  and  carbon  disulphide,  when 
passed  through  a  tube  containing  heated  copper,  i-eact  to 
form  copper  sulphide  and  methane : 

2  H2S  +  €82  +  4  Cu  =  4  CuS  +  CH4 

Other  methods  will  be  described  for  the  formation  of 
methane  from  certain  of  its  derivatives  later. 

Properties :  Methane  is  a  colorless  and  odorless  gas. 
Its  specific  gravity  is  0.559,  air  being  taken  as  1.  When 
subjected  to  a  pressure  of  140  atmospheres  it  liquefies  at 
0°  C.  Its  boiling  point  is  -162°  C.  and  it  solidifies  at 
-186°  C.  The  electric  sparks  from  an  induction  coil  de- 
compose methane  into  carbon,  which  is  deposited  as  a 
black  soot,  and  hydrogen  gas.  The  strongest  oxidizing 
agents,  such  as  nitric  and  chromic  acids,  scarcely  attack 
it,  and  concentrated  sulphuric  acid  and  alkalies  have  no 
action  upon  it.  It  is  therefore  one  of  the  most  stable 
and  inert  of  chemical  compounds.  On  being  led  through 
a  red-hot  tube  it  is  split  up  in  part  into  its  elements, 


The  Fatty  Compounds  3 

carbon  and  hydrogen,  but  in  part  forms  more  complex 
hydrocarbons  containing  carbon  chains,  which  will  be 
described  later  (6).  It  burns  with  a  faintly  luminous 
flame.  When  mixed  with  air  or  oxygen  it  forms  a  vio- 
lently explosive  mixture,  carbon  dioxide  and  water  being 
formed  : 


CH4  +  2  O2  =  Cft  +  2  H2O 

This  is  the  reaction  which  occurs  when  the  fire  damp 
of  mines  explodes. 

2.  Formation  of  Derivatives  of  Methane.  —  Chlorine 
or  bromine  react  with  methane  forming  respectively 
chlor  and  brom  methanes.  Methane  mixed  with  chlorine 
is  easily  exploded.  If  two  atoms  of  chlorine  (one  mole- 
cule) be  present  in  the  mixture  for  each  molecule  of  me- 
thane, the  following  products  represent  the  principal 
reaction:  CHl  +  C12  =  CH3C1  +  HC1 

Methyl 
chloride 

The  methane  molecule  less  one  H  atom  is  known  as  the 

* 

methyl  group  or  radical. 

Methyl  chloride  is  a  colorless  gas  of  a  pleasant  ethereal 
odor  which  boils  at  -23.7°  C.  It  is  slightly  soluble  in 
water  (4  volumes  in  1  of  H2O)  and  can  be  easily  freed  from 
hydrochloric  acid  by  washing.  Methyl  chloride  is  used  for 
producing  low  temperatures  artificially.  When  strongly 
compressed  the  volume  of  the  gas  is  greatly  decreased 
and  it  becomes  hot.  If  it  is  cooled  as  ft  is  compressed  until 
it  is  under  a  great  pressure  and  is  at  the  ordinary  tempera- 
ture, and  is  then  relieved  of  its  pressure,  it  expands  again 
and  its  temperature  falls  far  below  the  surroundings. 


4    Organic  Chemistry  for  Students  of  Medicine 

Water  in  contact  with  pipes  in  which  the  expansion  is 
allowed  to  take  place  is  frozen. 

Methyl  chloride  is  a  good  solvent  for  the  ethereal  oils 
and  is  employed  for  extracting  the  odors  from  flowers. 
Its  extraordinary  volatility  makes  it  possible  to  separate 
the  solvent  from  the  extracted  odorous  substances,  which 
are  themselves  very  volatile. 

Methyl  chloride  may  also  be  called  chlor methane. 
Either  of  these  names  gives  an  idea  of  the  nature  of  the 
substance  and  from  what  mother  substance  it  is  derived. 

The  chlorine  atom  in  methyl  chloride  behaves  very  dif- 
ferently from  that  in  the  halides  of  the  metals.  The  latter 
give  with  silver  nitrate  a  precipitate  of  silver  halide. 
Methyl  chloride  gives  a  precipitate  of  silver  chloride  only 
very  slowly  when  left  long  in  contact  with  silver  nitrate  in 
solution. 

This  difference  in  behavior  is  due  to  the  fact  that  in 
solutions  of  the  metallic  halides  the  chlorine  is  dissociated 
from  the  metal  to  a  considerable  extent  as  chlorine  ion: 

NaCl  ^±  Na+  +  01" 

In  the  dissociated  condition  the  chlorine  ion  carries  a 
charge  of  negative  electricity,  and  when  a  current  of  elec- 
tricity is  passed  through  a  solution  of  sodium  chloride  the 
Na+  ion  migrates  to  the  negative  pole  and  the  Cl~  ion  to  the 
positive  pole,  thus  transporting  the  charges  which  they 
carry.  They  are  therefore  conductors  of  electricity. 
Methyl  chloride  is  not  appreciably  ionized  when  in  solu- 
tion, and  does  not  therefore  conduct  the  electric  current. 
Its  low  rate  of  reactivity  with  AgNOs  is  also  the  result  of 


The  Fatty  Compounds  5 

its  nearly  undissociated  condition.  In  general  molecules 
do  not  react  with  each  other,  but  chemical  change  is  usually 
the  result  of  the  property  of  compounds  which  causes  them 
to  dissociate  into  simpler  parts  which  are  in  a  much  more 
active  state  chemically  than  the  molecule  from  which  they 
were  formed.  Since  methyl  chloride  does  react  very  slowly 
with  AgNOs  it  is  believed  by  many  chemists  to  be  in  a 
very  slight  degree  dissociated. 

A  compound  such  as  CH*,  in  which  all  the  valences  of 
each  of  the  atoms  it  contains  are  saturated,  should  theo- 
retically show  no  tendency  to  react  with  other  chemical 
substances.  The  reason  why,  e.g.,  chlorine  dges  react 
with  methane  is  best  explained  by  the  theory  elaborated 
by  Nef,  which  postulates  a  very  slight  dissociation  of 
methane  into  methylene  and  hydrogen  : 

/        H 


H 

These  components  are  in  dynamic  equilibrium  with  each 
other.  This  means  that  any  agent  which  removes  one  of 
the  dissociation  products  will  induce  the  further  dissocia- 
tion of  a  part  of  the  CH  molecules  to  maintain  certain 
relationships  with  respect  to  the  three  components  of  the 
system.  Only  the  dissociation  products  are  active  chemi- 
cally so  that  the  speed  of  reaction  will  be  determined  by 
the  degree  of  dissociation  of  the  methane.  This  is  greater 
at  higher  temperatures  than  at  lower,  so  that  reactions  of 
this  sort  are  greatly  accelerated  by  heat.  According  to 
this  theory  the  reaction  of  methane  with  chlorine  takes 
place  in  the  following  way  : 


6    Organic  Chemistry  for  Students  of  Medicine 


/ 


\ 

Methylene 


H         H     Cl      H     H 

I ;      1+1=1+1 

H         H     Cl      Cl    Cl 


/       H  /        Cl 

CH2  +  |   =  CHsCl;      CH2  +  |   =  CH2C12 
\       Cl'  \        Cl 


Methyl 

chloride 

(chlormethane) 


Methylene 

chloride 
(dichlormethane) 


4~WT 


Simultaneously  some  of  the  active  methylene  groups  should 
theoretically  react  with  each  other  forming  molecules  with 
two  carbon  atoms,  etc.  This  theory  is  in  accord  with 
the  observed  facts,  viz.  that  the  reaction  of  methane  with 
chlorine  does  not  lead  to  the  formation  of  a  single  prod- 
uct, but  of  several  products  simultaneously.  In  repre- 
senting the  reactions  between  organic  compounds  among 
themselves  and  with  inorganic  substances,  the  equation 
itten  represents  the  principal  reaction  only.  Further 
evidence  in  support  of  this  belief  will  be  presented  later. 
3.  The  Geometrical  Structure  of  Methane.  —  The  ex- 
perience of  many  chemists  has  shown 
that  the  relationship  which  exists  be- 
tween the  very  numerous  organic  com- 
pounds can  be  expressed  in  a  very  useful 
way  by  assuming  that  the  atoms  which 
make  up  the  molecules  occupy  definite 
relations  to  each  other  in  space.  The 
carbon  atom  is  conceived  to  have  its 
four  affinities  directed  toward  the  angles 
of  a  regular  four-sided  figure  (tetrahedron),  the  C  atom  it- 
self occupying  the  center  (Fig.  1). 


FIG.  1 


The  Fatty  Compounds 


Methane  is  expressed  by  the  spatial  formula  shown  in 
Figure  2,  the  hydrogen  atoms  forming  a  system  of  satellites 


FIG.  2 


FIG.  3 


about  the  C  atom  which  may  be  likened  to  the  sun  and  the 
planets  of  the  solar  system.     Chlormethane  or  methyl 
chloride  is  represented  by  the  structure  in  Figure  3. 
H 


CH4 


(d) 


This  formula  is,  however,  so  cumbersome  to  write  that 
in  ordinary  practice  it  is  not  employed.  Figure  4  shows 
the  various  types  of  simplified  figures  employed  to  describe 
the  carbon  atom  and  its  many  derivatives  produced  by  the 


8     Organic  Chemistry  for  Students  of  Medicine 

substitution  of  its  hydrogen  atoms  by  other  elements  or 
complexes. 

Of  these  symbols  CH4  is  employed  in  all  ordinary  cases 
in  writing  formulae.  It  is  known  as  the  empirical  formula, 
the  geometrical  arrangement  being  employed  only  for 
special  demonstration.  The  student  should  accustom 
himself  to  visualize  the  spatial  formulae. 

Now  in  Figure  2  each  of  the  four  hydrogen  atoms  occu- 
pies the  same  relative  position  with  respect  to  the  C  atom 
and  it  should  make  no  difference  whether,  in  making 
chlormethane,  we  substitute  one  hydrogen  atom,  or  an- 
other, by  the  chlorine.  The  methyl  chloride  should  have 
the  same  configuration  in  each  case,  which  is  equivalent  to 
saying  that  only  one  methyl  chloride  is  possible.  This 
is  in  accord  with  experience.  No  matter  how  methyl 
chloride  be  prepared,  and  there  are  several  methods 
for  its  preparation,  the  product  always  has  the  same 
specific  gravity,  boiling  point,  and  other  physical 
properties. 

In  assigning  four  valences  to  carbon,  it  should  be  borne 
in  mind  that  there  is  one  very  common  compound,  carbon 
monoxide,  CO,  in  which  carbon  must  exist  in  the  divalent 
state,  or  with  two  of  its  valences  polarized  or  latent.  In  a 
number  of  its  compounds  carbon  shows  a  marked  tendency 
to  pass  from  the  tetravalent  into  the  divalent  state,  or 
vice  versa.  This  is  seen  in  the  relation  between  carbon 
dioxide  and  carbon  monoxide  (also  called  carbonic  oxide). 
At  ordinary  temperatures  CO2  is  a  stable  gas,  but  under 
the  influence  of  the  silent  electrical  discharge  it  tends  to 
change  into  CO  +  O.  Carbon  monoxide  on  the  other 


The  Fatty  Compounds  9 

hand  can  readily  add  on  certain  elements,  as  chlorine,  and 
pass  back  into  the  tetravalent  state. 

CO  +  O    =  CO2 
CO  +  C12  =  COC12 

Carbonyl 
chloride 

The  latter  reaction  takes  place  very  slowly  in  the  dark, 
but  is  greatly  accelerated  by  sunlight.  Most  organic 
substances  exhibit  this  tendency  to  pass  in  some  degree  into 
labile  active  forms. 

4.  If  in  a  mixture  of  methane  and  chlorine  the  latter  is 
present  in  excess  two,  three,  or  four  hydrogen  atoms  are 
substituted  by  chlorine.  These  are  called  dichlor,  trichlor, 
and  tetrachlor  methane,  respectively.  Since  the  group 
CH2  is  termed  methylene  (2),  dichlormethane  is  sometimes 
called  methylene  chloride.  Trichlormethane  is  chloroform, 
a  familiar  substance  employed  as  an  anesthetic.  Tetra- 
chlormethane  is  familiarly  known  as  carbon  tetrachloride. 
It  is  much  employed  as  a  solvent  for  fats  and  oils,  and  is 
used  in  the  dry  cleaning  of  clothes.  Its  action  is  to  dis- 
solve the  grease  from  spots  and  when  the  latter  is  removed 
from  the  fabric  the  dirt  which  adhered  to  the  grease 
readily  separates.  Both  chloroform  and  carbon  tetra- 
chloride are  non-inflammable. 

There  are  bromine  and  iodine  substitution  products  of 
methane,  entirely  analogous  to  the  chlorine  compounds. 
Some  of  these  are  of  great  interest  and  value  in  synthetic 
work.  While  chlorine  reacts  with  methane  at  ordinary 
temperatures,  forming  substitution  products  and  hydro- 
chloric acid,  bromine  must  be  heated  in  a  sealed  tube  before 


10     Organic  Chemistry  for  Students  of  Medicine 

any  reaction  will  take  place,  and  iodine  will  not  react  with 
methane,  even  under  pressure  and  at  high  temperatures, 
to  form  substitution  products. 

5.  Methyl  Iodide.  —  For  the  preparation  of  the  iodine 
derivatives  advantage  is  taken  of  the  greater  affinity  of 
the  mono-  and  divalent  metals  for  chlorine  than  has  the 
methyl  radical,  thus  : 

CH3C1  +  KI  =  CH3I  +  KC1 

Methyl 
iodide 

Methyl  iodide  is  a  heavy  liquid  with  a  pleasant  ethereal 
odor,  boiling  at  43°  C.  Its  specific  gravity  is  2.  19.  It  is  so 
unstable  that  on  keeping  it  decomposes,  setting  free  iodine. 

6.  Ethane,  C2He. 

f^U  \ 

Zinc   methyl:    „*  >Zn  is  a  derivative  of  methane 
CH3/ 

which  is  formed  when  methyl  iodide  is  warmed  with  a 
mixture  of  zinc  and  copper  in  a  powdered  form.  The 
reaction  may  be  represented  as  follows  : 

CH3I  +  Zn  =  CH3—  Zn—  I 
2CH3-Zn—  I  =  ZnI2 


Zinc  methyl  is  a  colorless  liquid  boiling  at  46°  C.,  which 
is  so  unstable  that  it  explodes  when  exposed  to  the  oxygen 
of  the  air.  It  is  therefore  a  highly  reactive  substance  and 
can  be  used  to  build  up  synthetically  other  hydrocarbons 
from  methane.  Zinc  methyl  reacts  readily  with  methyl 
iodide  to  form  ethane  : 


CH3—  CH3 

Ethane 


The  Fatty  Compounds  11 

It  can  also  be  prepared  by  the  reaction  of  Wurtz  and 
Fittig,  in  which  methyl  iodide  is  allowed  to  react  with 
metallic  sodium : 

2  CH3I  +  2  Na  =  CHg— CH,  +  2  Nal 

Certain  metallic  derivatives  of  methane  and  ethane  are 
of  biological  importance.  Animals  poisoned  with  tellu- 
rium or  selenium  compounds  eliminate  in  the  breath  di- 
methyl telluride  CH3 — Te — CH3  and  dimethyl  selenide 
CH3 — Se — CH3  respectively.  These  possess  characteristic 
odors,  that  of  dimethyl  telluride  resembling  garlic.  The 
organism  is  thus  capable  of  employing  the  methyl  radical 
to  combine  with  these  toxic  elements  in  order  to  produce 
volatile  derivatives  which  can  be  eliminated. 

Dimethyl  telluride  is  a  heavy  yellow  oil  which  boils 
at  82°.  Dimethyl  selenide  is  a  liquid.  When  certain 
molds,  especially  Penicillium  brevicaule,  are  grown  upon 
media  containing  arsenic,  they  produce  volatile  diethyl 

/"^TT  PTT  v 

arsine,  ^^ ^^2  \A.sH,  which  has  a   garlic-like  odor. 

The  test  is  so  delicate  that  even  0.00001  gram  of  arsenic 
can  be  detected  with  certainty. 

It  is  through  the  agency  of  such  molds  that  poisoning 
with  arsenic  has  resulted  from  the  use  of  wall  paper  printed 
with  arsenic-containing  pigments. 

From  its  method  of  formation  ethane  is  therefore  believed 
to  be  made  up  of  a  methane  molecule  in  which  one  hydro- 
gen atom  is  substituted  by  a  methyl  group.  Its  structure 

NOTE.  —  Unless  otherwise  specified  all  temperatures  refer  to 
the  Centigrade  scale. 


12    Organic  Chemistry  for  Students  of  Medicine 


is  assumed  to  be  that  shown  in  Figure  5  (a)  and  (b),  but 
for  simplicity  the  formulae  (c),  (d),  or  (e)  are  employed. 

Ethane  may  be  regarded  as  methyl  methane  and  is 
occasionally  spoken  of  as  dimethyl.  It  is  a  colorless  and 
odorless  gas  which  is  liquefied  at  4°  by  46  atmospheres 
pressure.  It  is  slightly  more  soluble  than  methane  in 
water  and  alcohol.  It  occurs  with  methane  in  natural  gas 
and  is  present  in  petroleum. 

The  property  of  the  carbon  atom  of  combining  with  other 
carbon  atoms  in  a  very  firm  union  to  form  carbon  chains 


H 


•H 


H 


H-C-H       CH3 
H 


C2H6 


(b) 


(c) 


FIG.  5. 


is  unique  among  the  elements.     Ethane  and  its  homologues 
are  very  stable  substances  and  very  resistant  to  reagents. 
Ethyl  chloride,  CH3 — CH2C1,  can  be  prepared  by  the 
action  of  chlorine  on  ethane  : 

CH3— CH3  +  2C1  =  CH3— CH2C1  +  HC1 

The  ethane  molecule  less  one  hydrogen  atom  is  called 
the  ethyl  radical  or  group.  Methyl,  ethyl,  and  their  higher 
homologues  are  frequently  called  alkyl  radicals  or  groups, 
and  their  halogen  derivatives  alkyl  halides. 


The  Fatty  Compounds  13 

Ethyl  chloride  is  a  sweet-smelling  liquid  boiling  at 
12.5°.  In  a  manner  entirely  analogous  to  the  forma- 
tion of  methyl  iodide,  ethyl  iodide  can  be  produced 
from  the  chloride  : 

CH3—  CH2C1  +  KI  =  CH3—  CH2I  +  KC1 

Ethyl  iodide 

Ethyl  iodide  boils  at  72°.  It  can  react  with  methyl 
iodide  to  produce  a  hydrocarbon  containing  three  carbon 
atoms,  called  propane  : 


I  +  CHal  +  2Na  =  CH3—  CH2—  CH3 

Propane 

This  synthesis  can  also  be  effected  by  the  action  of  zinc 
methyl  on  ethyl  iodide  : 


CH3  \  ICH2 — CH3      CH3 — CH2 — CH3 

>Zn  + 
CH3/  ICH2— CH3      CH3— CH2— CH3 


If  metallic  sodium  be  allowed  to  act  on  ethyl  iodide,  two 
ethyl  radicals  are  combined  to  form  butane : 

CHa— CH2I  +  ICH2— CH3  =  CH3— CH2— CH2— CH3 

Butane 

Since  it  will  be  necessary  later  to  speak  of  the  dihalogen 
derivatives  of  ethane  in  illustrating  the  structure  of  certain 
compounds  (aldehydes),  mention  should  here  be  made  of 
the  nomenclature  of  these. 

When  two  of  the  hydrogen  atoms  of  ethane  are  replaced 
by  halogen,  two  compounds  are  possible  according  to 
whether  the  halogen  atoms  are  attached  to  the  same  or  to 
different  carbon  atoms. 


14     Organic  Chemistry  for  Students  of  Medicine 
CH2C1 


and 
CH2C1  CHC12 

Ethylene  Ethylidene 

chloride  chloride 

The  symmetrical  isomer  is  distinguished  by  the  ending  ene 
and  the  unsymmetrical  isomer  by  the  ending  idem  pre- 
ceded by  the  prefix  denoting  the  hydrocarbon  from  which 
it  was  derived.  Compounds  of  this  class  will  be  con- 
sidered later  (31). 

7.  Starting  with  methane,  therefore,  it  is  possible  to  build 
up  a  series  of  hydrocarbons  each  differing  from  the  next  lower 
one  by  a  CH2  group.  Their  formulae,  CH,  C2H6,  C3H8, 
C4Hio,  C5Hi2,  C6Hi4,  etc.,  all  correspond  to  the  general  ex- 
pression C»H2n+2.  They  have  the  general  name  of  saturated 
hydrocarbons,  because  all  the  valences  of  the  carbon  atoms 
not  holding  other  carbon  atoms  are  saturated  with  hydro- 
gen, so  that  they  cannot  take  up  any  more  of  the  latter. 

Nomenclature.  —  The  saturated  hydrocarbons  are  de- 
signated by  the  termination  "  ane."  Methane,  ethane,  pro- 
pane, and  butane,  have  special  names.  The  higher  ones 
are  denoted  by  the  Greek  or  Latin  numeral  signifying 
the  number  of  carbon  atoms  they  contain.  Thus,  C6Hi4  is 
called  hexane  ;  Ci0H22,  decane  ;  CieHw,  hexadecane  ;  etc. 

The  groups  of  atoms  which  are  derived  from  the  hydro- 
carbons by  the  removal  of  a  hydrogen  atom  are  termed 
alkyl  groups  ;  they  are  denoted  by  changing  the  ending 
"  ane  "  to  "  yl."  Thus  CH3—  ,  is  methyl  ;  C2H5—  ,  ethyl  ; 
C3H7  —  ,  propyl  ;  C4H9  —  ,  butyl  ;  etc. 

Properties  of  the  paraffins.  The  compounds  of  this 
series  containing  from  1  to  4  carbon  atoms  are  gases  ;  those 


The  Fatty  Compounds  15 

with  5  to  16  carbon  atoms,  liquids  at  ordinary  temperatures 
and  pressures;  while  those  having  more  than  16  carbon 
atoms  in  the  molecule  are  solids.  Members  containing 
from  1  to  60  carbon  atoms  are  actually  known. 

8.  Crude  Petroleum,  which  occurs  in  nature  in  enor- 
mous quantities,  consists  of  a  mixture  of  all  the  members 
of  the  series  from  the  lowest  to  the  highest.  When  distilled 
the  lower  members  volatilize  first,  the  temperature  in  the 
still  rising  as  the  distillation  proceeds.  The  lightest 
fraction  which  is  collected  distills  at  0°  and  consists  of 
gases,  chiefly  butane,  which  are  liquefied  under  pressure 
and  employed  for  the  production  of  cold  by  evaporation. 
As  a  rule  the  distillate  is  collected  until  the  product  coming 
over  has  a  specific  gravity  of  .729.  This  is  reached  at  a 
temperature  of  about  150°,  at  which  point  chiefly  nonane 
and  decane  distill.  All  the  product  so  obtained  is  known 
as  crude  naphtha.  This  is  redistilled  and  separated  into 
rhigolene  B.  P.  18°,  petroleum  ether  or  naphtha  B.  P.  50-60, 
containing  chiefly  CsH^  and  CeHi4;  benzine  B.  P.  70- 
90°,  chiefly  C6Hi4  and  C7Hi6;  ligroin  B.  P.  90-120°,  and 
petroleum  benzine  B.  P.  120-150°,  chiefly  mixtures  of 
C7Hi6  and  C8Hi8.  From  150-300°  there  is  collected  the 
"  burning  oil  distillate,"  which  is  redistilled  into  several 
grades  of  kerosene.  The  safety  of  these  oils  depends  on 
their  volatility,  for  their  vapors  mixed  with  air  form 
explosive  mixtures.  Their  use  is  attended  with  consider- 
able danger.  The  quality  of  the  product  is  determined  by 
the  flash  point  and  "  burning  point."  These  are  deter- 
mined by  heating  a  sample  in  a  dish  and  at  intervals  bring- 
ing a  small  flame  near  the  surface.  When  vapors  are 


16     Organic  Chemistry  for  Students  of  Medicine 


given  off  rapidly  enough  to  form  a  combustible  mixture, 
there  is  a  flash,  which  is  at  once  extinguished.  At  a  higher 
temperature  vapors  are  given  off  rapidly  enough  to  support 
a  flame.  This  is  known  as  the  burning  point.  Most 
states  require  a  flash  point  of  at  least  110°  F.  and  a  burning 
point  of  110  to  150°  F. 

Above  300°  F.  there  are  distilled  various  grades  of 
lubricating  oils.  From  the  residues  vaseline  and  paraffin 
are  separated,  the  latter  by  chilling. 

The  physical  constants  of  a  number  of  the  normal 
hydrocarbons  are  given  below : 

TABLE  I 


MELTING 
POINT 

BOILING  POINT 

SPECIFIC 
GRAVITY 

CH4      Methane 

-  184° 

-  164° 

.415  at  16.4° 

C2H6     Ethane 

-  172.1 

-84.1 

.446 

C3Hg     Propane 

-45 

-44.5 

.535 

40° 

C4Hio    Butane 

— 

-    1 

.600 

CsH^    Pentane 

— 

36.3 

.454 

CeHi4    Hexane 

— 

69 

.660 

CyHie    Heptane 

— 

98.3 

.683  1  at  20° 

C8Hi8    Octane 

— 

125.8 

.702 

Ci6H34  Hexadecane 

18 

287 

.775' 

CiyHse  Heptadecane 

22 

303 

.777 

CisH38  Octadecane 

28 

317 

.777 

* 

At  thp 

C27H56  Heptacosane 

60 

270 

.780    M    p~ 

C3iHe4  Hentriacontane 

68 

302 

At 

.781 

C32H66  Dotriacontane 

70 

310 

15  mm. 

.781 

C35H72  Pentatriacon- 

pressure 

tane 

75 

331 

.  - 

.782  J 

The  Fatty  Compounds  17 

9.  Isomerism.  *—  Just  as  in  the  case  of  methane,  there 
is  but  one  substance  known  having  the  formula  CH4,  so 
there  is  but  one  compound  having  the  formula  C^He 
(ethane),  and  one  having  the  formula  C3H8  (propane). 
Butane,  C4Hi0,  however,  exists  in  two  forms.  They  have 
the  same  percentage  composition  with  respect  to  carbon 
and  hydrogen,  and  the  same  molecular  weight,  but  differ 
in  their  boiling  points  and  specific  gravities.  Both  are 

H  H  H 

1.1  I 

H-C-H        H-C-H         H-C-H 

H-C-H  H-C-H  H-CH^l 
I                       I  I 

H-C-H  H-C-H  H-C-H 

I  I  1 

H  Cl  H 


(a)  (&)  (c)  (d) 

FIG.  6. 

gases,  but  one  is  liquefied  at  —  1°  while  the  other  remains  a 
gas  until  cooled  to  -  17°.  The  existence  of  two  or  more 
compounds  having  the  same  chemical  formula  but  different 
physical  properties  is  explained  by  the  structural  formulas. 
Thus  while  all  the  hydrogen  atoms  in  methane  and  ethane 
are  alike  with  respect  to  the  remainder  of  the  molecule ;  in 
propane  and  butane  and  the  higher  homologues  this  is 
not  the  case,  as  is  illustrated  in  Figure  6. 

If  in.(fr)  a  chlorine  atom  should  be  substituted  for  a 
hydrogen  atom,  the  same  chlor  propane  or  propyl  chloride 
should  result  whichever  one  of  the  hydrogen  atoms 
attached  to  either  end  carbon  atom  might  be  replaced, 


18     Organic  Chemistry  for  Students  of  Medicine 


but  a  different  compound  should  result  provided  the 
chlorine  should  be  substituted  for  a  hydrogen  attached  to 
the  middle  carbon  atom.  This  C  atom  differs  from  the 
two  end  ones  in  that  two  of  its  valences  are  in  union  with 


Normal  butane 


Isobutane 


H 

H-C-H 
H-C-H 
H-C-H 

H-C-H 

I 
H 


H 

H-C-H 
H-C-CH8 


H-C 

I 
H 


H 


Normal  butane  Isobutane 

(methyl-ethyl-  (trimethyl 

methane)  methane) 

FIG.  7. 

methyl  groups,  while  the  others  are  each  linked  to  carbon 
by  only  one  bond.  Theory  calls  therefore  for  only  one 
propane,  and  only  one  is  known,  while  it  calls  for  two 
mono-chlor  propanes  and  both  of  these  are  known.  Nor- 
mal propyl  chloride,  CH3 — CH — CHaCl,  abbreviated 


The  Fatty  Compounds  19 

rc-propyl  chloride,  boils  at  46.4°,  while  isopropyl  chloride, 
CH3—  CHC1—  CH3,  boils  at  36.5°. 

We  should  expect  in  the  case  of  butane  two  forms  corre- 
sponding to  the  propyl  chlorides,  the  methyl  group  occupy- 
ing the  position  of  the  chlorine  atoms  (Fig.  7). 

Isobutane  consists  of  a  branched  chain  of  carbon  atoms, 
normal  butane  does  not.  Such  a  difference  in  structure 
is  called  isomerism  and  the  compounds  so  related  are 
isomers.  Normal  butane  may  be  looked  upon  as  methyl- 
ethyl-methane,  since  two  hydrogens  are  respectively 
substituted  by  a  methyl  and  an  ethyl  radical. 

Three  pentanes  should  exist  if  our  theory  of  structure 
is  correct  and  as  a  matter  of  fact  three  are  known  : 

CH3  CH3   CH3 

CH2  CH 

CH2  CH2 

CH3 


i 
CH3 

n-pentane  (methyl-  Dimethyl-ethyl-  ,  Tetramethyl-methane 

propyl-methane)  methane 

The  boiling  points  of  the  normal  hydrocarbons  are 
always  higher  than  those  of  the  isomers,  and  the  boiling 
point  becomes  continuously  lowered  the  more  the  carbon 
chain  is  branched,  i.e.  the  more  the  methyl  groups  are 
gathered  together  in  the  molecule. 

The  constitution  of  the  hydrocarbons  of  the  paraffin 
series  can  be  arrived  at  only  by  their  synthetical  formation 


20     Organic  Chemistry  for  Students  of  Medicine 

from  simpler  ones  of  known  structure.  Thus,  by  the 
Wurtz  reaction  one  molecule  of  normal  propyl  iodide  and 
one  of  ethyl  iodide  can  yield  one  molecule  of  normal 
pentane  (1)  ;  one  molecule  of  isopropyl  iodide  and  one  of 
ethyl  iodide  can  yield  dimethyl-ethyl-methane  (2)  ;  and 
from  one  of  the  isobutyl  iodides  and  methyl  iodide  are 
obtained  tetramethyl  methane  (3)  : 


(1)  CHs—  CH2—  CH2I  +  ICH2^-CH3  +  2  Na 

=  CH3—  CH2—  CH2—  CH2—  CH3  +  2  Nal 
CH3 

(2)  ">CHI  +  ICH2—  CH3  +  2  Na 

CHs 

CH3\ 

:H—  CH2—  CH3  +  2NaI 


CH3\ 

00 


CH3/ 

CH3 


+  ICH3+2Na  = 


The  number  of  possible  isomers  increases  very  rapidly 
with  increasing  carbon  atoms.  The  following  table  shows 
the  number  theoretically  possible  for  some  of  them : 

NUMBER  OP  ISOMERS 

Hexane  CeH^  5  Decane       Ci0H22  75 

Heptane  C7Hi6  9  Undecane   CnH24  159 

Octane  C8Hi8  18  Dodecane   Ci2H26  354 

Nonane  C9H20  35  Tridecane  Ci3H28  802 


The  Fatty  Compounds  21 

Most  of  these  compounds  have  never  been  prepared 
because  they  are  not  of  sufficient  importance  to  induce 
chemists  to  give  the  necessary  effort.  The  methods  of 
forming  them  are  well  understood  and  it  is  quite  possible 
to  produce  large  numbers  of  them  synthetically. 

10.  A  carbon  atom  which  is  only  linked  to  one  other 
carbon  atom  is  called  primary  ;  one  which  is  linked  to  two 
carbon  atoms  is  secondary  ;  one  linked  to  three  is  tertiary  ; 
and  to  four,  quaternary.  When  situated  at  the  end  of  a 
chain  a  carbon  atom  is  called  terminal.  The  carbon  atoms 
of  a  chain  are  designated  by  numbers,  the  terminal  one 
being  denoted  by  1,  the  next  by  2,  etc.,  for  example  : 


OJH.3  -  O  Jl2  -  O  A12  -  V-/-H.2 

12345 
Frequently  the  longer  chains  are  written 
CH3—  (CH2)n—  CH3. 

The  terminal  carbon  atom  is  frequently  denoted  by  o>, 
the  Greek  letter  omega,  the  next  by  «  (alpha)  and  the 
succeeding  ones  by  /3,  7,  etc.  Methane  and  its  homo- 
logues  are  collectively  spoken  of  as  the  methane  series,  or 
the  paraffin  hydrocarbons. 

11.  The  assumption  that  the  four  valences  of  the  carbon 
atom  are  directed  toward  the  angles  of  a  regular  tetrahe- 
dron does  not  necessitate  regarding  their  positions  with 
respect  to  each  other  as  fixed.  There  is  good  reason  to 
believe  that  they  may  revolve  around  a  position  of  equi- 
librium without  changing  the  order  of  succession. 


CHAPTER  II 
THE  ALCOHOLS 

12.  The  Monatomic  Alcohols. — When  methyl  chloride, 
bromide,  or  iodide  is  warmed  with  water,  halogen  acid  and 
a  new  substance,  methyl  alcohol,  are  formed.  It  may  be 
looked  upon  as  water  in  which  one  H  atom  is  replaced  by 
the  CH3  radical. 

CH3C1  +  HOH  =  CH3OH  +  HC1 

Methyl 
alcohol 

Its  synthetic  formation  has  only  a  scientific  interest,  for 
in  practice  it  is  always  obtained  as  a  by-product  of  wood 
distillation. 

The  alcohols  and  the  corresponding  alkyl  halides  are  in 
general  mutually  transformable  into  each  other.  Thus 
on  treatment  with  phosphorus  pentachloride  the  alcohols 
are  converted  into  alkyl  chlorides,  the  OH  group  being 
replaced  by  Cl : 

CH3— CH2OH  +  PC15  =  CH3— CH2C1  +  POC13  .+  HC1 

Phosphorus 
oxy  chloride 

It  is  customary  in  illustrating  reactions  which,  like  this 
one,  are  characteristic  of  a  series  by  employing  the  symbol 
R  in  place  of  the  alkyl  group  attached  to  carbinol,  as  : 

R— CH2OH  +  PC15  =  R— CH2C1  +  POC13  +  HC1 

22 


The  Alcohols  23 

Methyl  alcohol  is  known  as  wood  alcohol  because  it  is 
produced  when  wood  is  heated  out  of  contact  with  the  oxy- 
gen of  the  air  to  a  temperature  sufficient  to  decompose  it. 

Properties.  The  methyl  alcohol  of  commerce  is  obtained 
in  this  way.  It  is  a  colorless  liquid  which  is  neutral  in 
reaction ;  that  is,  it  does  not  dissociate  H+  or  OH~  ions,  a 
fact  which  is  shown  by  its  failure  to  act  on  indicators  such 
as  litmus,  or  to  conduct  the  electric  current.  It  is  soluble 
in  water  in  all  proportions,  has  a  burning  taste,  and  boils 
at  64.5°. 

Methyl  alcohol  is  the  lowest  member  of  a  homologous 
series  of  alcohols  derived  from  the  hydrocarbons  of  the 
methane  series,  the  second  member  being  ethyl  alcohol 
CH3— CH2OH. 

13.  Nomenclature  of  the  Alcohols.  —  Certain  of  the 
more  common  alcohols  have  received  special  names  which 
they  retain  as  the  result  of  long  usage.  In  the  systematic 
nomenclature  usually  employed  they  are  regarded  as 
derivatives  of  carbinol  or  methyl  alcohol.  This  system 
is  of  especial  utility  in  indicating  the  structures  of 
the  isomeric  alcohols.  Thus  ethyl  alcohol  is  methyl 
carbinol,  CH3CH2OH,  and  the  two  primary  butyl  al- 
cohols are  propyl  carbinol  and  isopropyl  carbinol. 
Further  examples  are  given  in  connection  with  the 
amyl  alcohols  (20). 

Another  system  of  nomenclature  which  is  frequently 
employed  is  that  of  using  the  name  of  the  hydrocarbon 
with  the  same  number  of  carbon  atoms  and  employing  the 
suffix  -ol  to  indicate  the  alcohol.  Thus  methyl  alcohol  is 
methanol;  ethyl  alcohol,  ethanol;  etc. 


24    Organic  Chemistry  for  Students  of  Medicine 


The  relationship  of  the  first  five  alcohols  to  the  cor- 
responding hydrocarbons  is  illustrated  by  the  following 
formulae : 


Methyl  alcohol 
Ethyl  alcohol 

Propyl  alcohol 
7i-Butyl  alcohol 
Isobutyl  alcohol 


CH3OH 
CH3— CH2OH 

CH3— CH2— CH2OH 

CH3— (CH2)2CH2OH 

CH3, 

>CH— CH2OH 
CH3/ 

CH3— (CH2)3— CH2OH 


Methanol,  carbinol. 

Ethanol,  methyl  car- 
binol. 

Propanol,  ethyl  car- 
binol. 

Butanol,  ra-Propyl  car- 
binol. 

Isobutanol,  Isopropyl 
carbinol. 

n-'Pentanol,  n-Butyl 
carbinol. 


n-Pentyl  alcohol 
(Amyl  alcohol) 

14.  Ethyl  Alcohol,  ethanol,  methyl  carbinol.  —  This  is 
the  ordinary  alcohol  obtained  by  fermentation  of  sugar  by 
yeasts.  It  occurs  in  all  fermented  liquids  such  as  wine 
and  beer.  It  is  made  chiefly  from  potatoes,  grains, 
and  molasses.  The  starch  is  converted  into  sugar  and 
the  latter  into  alcohol  and  carbon  dioxide.  The  -chemical 
reactions  involved  in  this  process  will  be  described  in  con- 
nection with  the  fermentation  of  sugars  (164). 

Ethyl  alcohol  is  prepared  technically  by  distilling  fer- 
mented solutions.  It  is  a  liquid  of  agreeable  odor, 
which  boils  at  78° ;  and  although  the  fermented  liquids 
never  contain  more  than  18%  of  alcohol,  by  carrying 
out  the  distillation  in  a  fractionating  column  alcohol  of 
84  to  90%  strength  may  be  obtained.  The  fractionating 
column  is  an  apparatus  in  which  a  relatively  large  cooling 
surface  is  offered  and  a  considerable  time  is  allowed  for 
the  condensation  of  the  less  volatile  liquid.  There  are 


The  Alcohols  25 

ordinarily  placed  in  the  vapors  ascending  from  the  still, 
obstructions  such  as  glass  beads  or  platinum  gauze,  to 
retard  their  escape,  thus  giving  greater  opportunity  for 
the  condensation  of  the  higher  boiling  liquid  of  the  mixture, 
which  then  runs  back  into  the  still.  The  lower  boiling 
constituent  escapes  condensation  and  passes  over  into  the 
receiver. 

On  redistilling  the  alcohol  thus  obtained  in  an  efficient 
rectifying  apparatus  a  product  containing  but  4%  of 
water  is  obtained.  This  strength  of  alcohol  is  much  used 
in  the  arts  as  a  solvent. 

Absolute  alcohol  is  obtained  by  treating  96  %  alcohol  with 
quicklime,  which  removes  the  water,  forming  calcium 
hydrate,  Ca(OH)2.  The  alcohol  is  then  rectified  again. 
The  product  so  obtained  contains  about  .5  %  of  water. 
This  is  the  commercial  absolute  alcohol.  Pure  absolute 
alcohol  is  obtained  by  treating  the  latter  with  a  small 
amount  of  metallic  sodium  or  calcium  and  distilling  again. 
Traces  of  water  in  alcohol  can  be  readily  detected  by 
placing  in  it  a  small  amount  of  copper  sulphate  from  which 
the  water  of  crystallization  has  been  driven  off  by  heating. 
This  is  a  white  powder.  The  anhydrous  CuSO4  takes 
up  even  very  slight  traces  of  water  from  the  alcohol  and 
forms  the  deep  blue  hydrated  salt. 

Among  inorganic  substances  alcohol  dissolves  the  halo- 
gens, sulphur  and  phosphorus  to  some  extent,  boracic  acid, 
the  hydrates  of  potassium  and  sodium,  the  chlorides  of 
calcium  and  strontium,  ferric  chloride  and  mercuric 
chloride.  It  is  also  a  solvent  for  many  organic  acids,  bases, 
and  neutral  substances,  the  resins,  soaps,  and  fats.  Alco- 


26     Organic  Chemistry  for  Students  of  Medicine 

holic  solutions  of  substances  employed  in  medicine  are 
called  essences,  spirits,  and  tinctures.  Certain  proteins  of 
the  cereal  grains  readily  dissolve  in  70  %  alcohol,  but  most 
proteins  are  precipitated  from  their  solutions  by  alcohol. 

For  use  in  the  arts  alcohol  is  now  sold  without  the  pay- 
ment of  the  internal  revenue  tax  which  is  levied  on  all 
alcoholic  beverages.  Such  alcohol  to  be  tax  free  must  be 
denatured  or  rendered  unfit  for  drinking  by  the  addition 
of  poisonous  and  distasteful  substances.  The  regulations 
of  the  United  States  Commissioner  of  Internal  Revenue 
prescribe  the  addition  of  10  parts  of  methyl  alcohol  and  1 
part  of  benzine  to  each  100  parts  of  alcohol.  Another 
formula  which  may  be  used  requires  the  addition  of  2  parts 
of  wood  alcohol  and  1  or  2  parts  of  pyridine. 

Ethyl  alcohol  is  widely  distributed  in  nature.  Small 
amounts  of  it  are  found  in  the  distillate  from  leaves, 
flowers,  in  the  ethereal  oils,  and  in  humus-rich  soil.  Traces 
occur  in  bread  made  with  yeast.  Very  small  amounts 
are  regularly  found  in  the  blood  and  tissues  of  animals. 
Indeed  there  are  strong  reasons  for  believing  that  in  the 
destruction  of  sugar  through  the  normal  physiological 
processes,  ethyl  alcohol  is  an  intermediate  product. 

15.  The  Alcoholates.  —  Metallic  sodium  reacts  with 
great  energy  on  alcohol,  forming  sodium  ethylate  and 
hydrogen : 

C2H5OH  +  Na  =  C2H5ONa  +  H 

Sodium  ethylate  is  readily  soluble  in  alcohol  and  forms 
a  crystalline  compound  C2H5ONa  +  2C2H5OH.  This 
loses  its  alcohol  at  200°,  leaving  the  sodium  ethylate  as 
a  white  powder.  It  is  very  useful  in  synthetic  work. 


The  Alcohols  27 

Potassium  acts  violently  on  alcohol,  forming  potassium 
ethylate. 

16.  Alcoholic  Beverages.  —  There  are  two  classes  of 
alcoholic  beverages  in  use :  those  which  are  the  direct 
product  of  fermentation  by  yeast ;  and  those  which  are 
prepared  by  distilling  the  fermented  liquid,  as  molasses 
or  extracts,  prepared  by  conversion  of  the  starches  of 
certain  grains,  potatoes,  etc.,  into  sugar,  and  dissolving 
out  the  latter.  The  undistilled  beverages  contain  much 
less  alcohol  than  the  distilled. 

Beer  is  prepared  by  fermenting  malted  (i.e.  sprouted) 
grains.  It  contains  3  to  5  per  cent  of  alcohol  and  derives 
its  bitter  taste  from  the  addition  of  an  infusion  of  hops. 

Wine  and  champagne  are  fermented  fruit  juices,  prin- 
cipally grape  juice.  As  fermented,  a  beverage  never  con- 
tains more  than  about  15  to  18  per  cent  of  alcohol,  but 
wines  are  frequently  "  fortified  "  by  the  addition  of  alco- 
hol to  a  content  of  20  %. 

Whiskey  is  prepared  by  the  fermentation  of  malted 
grains.  After  the  fermentation  by  yeast  is  completed,  the 
product  is  distilled  and  the  distillate  condensed.  Ordina- 
rily it  is  twice  distilled  and  water  is  added  to  the  distillate 
to  make  a  solution  containing  about  50  to  58  %  of  alcohol 
by  volume. 

Brandy  is  made  by  distilling  wines  or  fermented  peach, 
apple,  or  other  juices.  Its  alcohol  content  varies  from 
44  to  55  %. 

Gin  is  whiskey  which  has  been  distilled  with  aromatic 
substances  such  as  juniper  berries,  anise  seed,  etc.,  which 
give  it  its  peculiar  flavor. 


28    Organic  Chemistry  for  Students  of  Medicine 

Rum  is  made  from  fermented  molasses.  It  not  infre- 
quently contains  enough  of  the  higher  alcohols,  butyl  and 
amyl  alcohols  and  their  esters,  to  render  it  more  toxic  than 
ordinary  whiskey  prepared  from  grains. 

17.   Higher  Homologues  of  Ethyl  Alcohol.  — 

CH4        CHs—  CH3  CH3—  CH2—  CHg 

Methane  Ethane  Propane 


CH,—  OH     CH3—  CH2OH     CHs—  CH2—  CH2OH 

Methyl  alcohol  Ethyl  alcohol  Propyl  alcohol 

CH3—  (CH2)2—  CH3         CH3—  (CH2)  g-CHa 

Butane  Pentane 

CH3—  (CH2)2—  CH2OH      CH3—  (CH2)  3—  CH2OH 

Butyl  alcohol  Amyl  alcohol 

Being  derived  from  the  hydrocarbons  of  the  CnH2n+2 
series  by  the  replacement  of  H  by  OH  these  alcohols  have 
the  general  formula  CnH2n+iOH.  Those  derived  from  the 
normal  hydrocarbons  are  normal  alcohols.  If  the  OH 
group  is  attached  to  an  end  carbon  atom  it  is  known  as  a 
primary;  if  to  a  secondary  carbon  atom,  a  secondary;  and 
if  to  a  tertiary  carbon  atom,  a  tertiary  alcohol.  Those 
derived  from  branched  chain  hydrocarbons  are  iso  alco- 
hols, and  may  be  primary  or  secondary  : 

CH3—  CH2—  CH2OH  CH3—  CH(OH)—  CH3 

Primary  propyl  alcohol  (normal)  Secondary  propyl  alcohol  (isopropyl  alcohol) 

18.  The    Butyl   Alcohols.  —  C4H9OH. 

SPECIFIC 

BOILINO  GRAVITY 

POINT  AT  20° 

1.  CHg—  CH2—  CH2—  CH2OH  117°  .810 

Normal  butyl  alcohol  (primary) 
(Propyl  carbinol) 


The  Alcohols  29 

2.  CH3   v 

;>CH— CH2OH  107°  .806 

CHa   ' 

Isobutyl  alcohol  (primary) 
(Isopropyl  carbinol) 

3.  CH3— CH2\ 

>CHOH  100°  .808 

CH3/ 

Normal  secondary  butyl  alcohol 
(Methyl  ethyl  carbinol) 

4.  CH3\ 

CH3^COH  83°  .786 

CH,/ 

Tertiary  butyl  alcohol 
(Trimethyl  carbinol) 

Normal  primary  butyl  alcohol  occurs  in  fusel  oil  to  a 
small  extent,  but  has  little  biological  importance.  It  is 
produced,  together  with  a  number  of  other  products,  by 
Bacillus  butylicus,  growing  on  glycerin  and  various  sugars 
and  related  substances  (see  butyric  acid  fermentation, 
164). 

The  most  important  butyl  alcohol  is  isopropyl  carbinol. 
It  is  produced  by  yeasts  during  fermentation  of  sugar 
into  ethyl  alcohol  and  carbon  dioxide.  It  has  its  origin 
not  from  sugar,  but  from  one  of  the  protein  digestion 
products,  valin.  It  is  formed  in  relatively  large  amounts 
when  potatoes  are  malted  and  fermented  by  yeasts,  be- 
cause the  mother  substance  valin  (73)  is  present  in 
greater  amount  than  in  the  malted  grains. 


30    Organic  Chemistry  for  Students  of  Medicine 

The  remaining  two  butyl  alcohols  have  been  prepared 
synthetically,  but  do  not  occur  in  nature. 

Physiological  properties.  —  The  butyl  alcohols  are  all 
distinctly  poisonous  both  to  plants  and  animals.  The 
toxic  action  of  monatomic  alcohols  increases  with  higher 
carbon  content  and  with  increasing  molecular  weight. 
This  is  the  Rule  of  Richardson.  The  normal  primary  al- 
cohol is  more  toxic  than  isopropyl  carbinol,  and  the  latter 
is  more  toxic  than  secondary  and  tertiary  butyl  alcohols. 

19.  The  Amyl  Alcohols.  — 


I* 


1.  Normal  primary    CH3-CH2-CH2-CH2-CH2OH    138°     .817 

(butyl  carbinol) 

2.  Isobutyl  carbinol   ^TT  \ 

(primary)  ^^>CH-CH2-CH2OH  130°     .810 

(Active  amyl  alcohol)       3/ 

3.  Secondary  butyl  ^\CH-CHsDH  128°      .816 
carbinol  (primary)    CH3  —  CH2/ 

/~<TT  v 

4.  Tertiary  butyl       CH3-^C-CH2OH  113°      - 
carbinol  (primary)    ^jj   / 

CH3 

5.  Methyl  propyl  ^>CHOH  119°      — 
carbinol  (secondary)  CHs  —  CH2  —  CH2 


6.  Methyl  isopropyl  CH3\         J>CHOH  112°     .819 
carbinol  (second-            yCH 

ary)  CH3/ 

CH3-CH2\ 

7.  Diethyl  carbinol  )>CHOH  117°      — 

CH3-CH2/ 


The  Alcohols  31 

8.  Dimethyl  ethyl  CH^-OH  102°      - 

carbmol   (tertiary)      ^^      ~u   / 

V^rls —  V^±l2/ 

The  only  two  amyl  alcohols  which  are  of  any  great  im- 
portance in  biological  processes  are  primary  isobutyl  carbinol 
and  secondary  butyl  carbinol.  These  both  occur  in  fusel  oil 
through  the  life  processes  of  yeasts,  and,  like  isobutyl  alco- 
hol, are  derived  from  the  cleavage  products  of  proteins  (75). 

Physiological  Properties.  —  All  have  disagreeable  smells 
and  produce  headache.  Normal  amyl  alcohol  is  about 
four  times  as  toxic  as  ethyl  alcohol.  A  .5  %  solution 
quickly  destroys  infusoria,  and  a  1  %  solution  kills  algae 
within  a  day.  In  dilutions  as  great  as  .1  %  certain  bac- 
teria can  use  it  as  a  source  of  carbon. 

A  saturated  (2.5  %)  solution  of  isoamyl  alcohol  exerts  a 
powerful  bactericidal  action.  The  toxicity  of  the  amyl  alco- 
hols is  distinctly  greater  than  that  of  the  lower  members  of 
the  series.  A  -fan  solution  is  as  destructive  to  B.  pyogenes 
as  a  -fan  solution  of  butyl,  a  -fan  solution  of  propyl,  a  I  fan 
solution  of  ethyl,  and  a  2?n  solution  of  methyl  alcohol. 

20.  Isomerism  of  the  Amyl  Alcohols.  —  One  of  the  amyl 
alcohols,  secondary  butyl  carbinol,  also  called  active  or 
fermentation  amyl  alcohol,  presents  a  very  interesting  case 
of  isomerism.  Three  isomers  of  this  one  alcohol  are  known, 
but  they  have  all  the  same  chemical  and,  with  a  single 
exception,  the  same  physical  properties.  This  exception 
is  found  in  their  action  on  polarized  light.  The  ray  of 
polarized  light  may  be  likened  to  a  ribbon  of  light,  as  con- 
trasted with  a  ray  of  ordinary  light  the  waves  of  which 
are  vibrating  in  every  direction  at  right  angles  to  the  path 


32    Organic  Chemistry  for  Students  of  Medicine 

of  the  ray.  In  the  polarized  ray  the  vibrations  all  lie  in 
the  same  plane.  When  such  a  ray  is  passed  into  either 
of  two  of  these  amyl  alcohols  the  ray  is  rotated  by  one  of 
them  to  the  right  and  by  the  other  to  the  left.  One  is  said 
to  be  dextrorotatory,  the  other  levorotatory  .  The  third  pro- 
duces no  rotation  at  all.  Two  are  said  to  be  optically  active  ; 
the  other,  inactive.  The  effect  is  as  if  the  ray  had  received 
a  twist  in  passing  through  the  optically  active  substance. 
Now  these  two  active  isomers  when  treated  with  gaseous 
HI  are  transformed  into  two  optically  active  amyl  iodides, 
and  the  inactive  one  into  an  amyl  iodide  which  is  not 
optically  active. 

CH3Nr/H 
CH3—  CH2A\CH2OH 

+  HI  CH3         H 


+  H20 
CH3—  CH2         CH2I 

The  amyl  iodides,  like  the  alcohols  from  which  they  were 
derived,  have  identical  chemical  and,  except  in  their  be- 
havior toward  polarized  light,  the  same  physical  properties. 
Suppose  we  consider  the  iodide  which  is  derived  from  levo- 
rotatory amyl  alcohol,  which  is  the  important  one  from  the 
biological  standpoint.  If  it  be  converted  into  pentane 
by  the  action  of  nascent  hydrogen,  which  removes  the 
iodine,  replacing  it  by  H,  there  results  a  pentane  which  is 
optically  inactive  : 

CH3\       /H       +2H  CH3\      /H 


CH3— CH2/       \CH2I  CH3— CH2/        \CH3 

Active  Inactive 


The  Alcohols  33 

On  the  other  hand,  if  this  iodide  is  caused  to  react  with 
ethyl  iodide  in  the  presence  of  sodium,  there  is  produced  a 
heptane  which  is  optically  active : 

CH3\     /H 

Xx 
CH3— CH2/        \CH2I  +  2Na  +  ICH2— CH3 

CH3\        /H 


CH3— CH2/        \CH2— CH2— CH3 

Methyl-ethyl-propyl-methane 
(Active) 

If  the  above  reaction  is  carried  out  with  methyl  iodide 
instead  of  ethyl  iodide  there  is  formed  a  hexane  which  is 
optically  inactive : 

CH3\        /H 

c\ 

CH3— CH2/        \CH2I  +  2Na  +  ICH3 

CHs\ 


CH3— CH2/         \CH2— CH3 


Methyl-diethyl-methane 
(Inactive) 

An  inspection  of  these  formulas  shows  that  those  com- 
pounds are  optically  active  in  which  each  of  the  bonds  of 
affinity  of  one  carbon  atom  is  linked  to  different  groups  or 
atoms.  Whenever  two  bonds  of  this  carbon  atom  are 
linked  to  the  same  kind  of  group  (as  two  methyl  or  two 
ethyl  groups)  the  optical  activity  is  lost. 

Van't  Hoff  first  discovered  that  optically  active  com- 
pounds have  in  general  at  least  one  carbon  atom  which  is 
D 


34     Organic  Chemistry  for  Students  of  Medicine 


linked  to  four  different  atoms  or  radicals.     He  gave  the 
name  "  asymmetric  "  carbon  atom  to  one  so  linked. 

Van't  Hoff  further  showed  that  the  existence  of  three 
isomers  must  necessarily  result  from  the  structure  of  an 
asymmetric  carbon  atom,  if  the  assumption  be  correct  that 
the  four  valences  of  the  carbon  atom  are  directed  as  to- 
ward the  four  solid  angles  of  a  regular  tetrahedron,  the 
carbon  atom  itself  occupying  the  center  of  the  figure. 

b  b 


FIG.  8. 


FIG.  9. 


With  such  an  arrangement  there  must  result  two  kinds  of 
molecules  which  resemble  each  other  in  the  same  way  as 
the  right  hand  resembles  the  left,  or  as  an  object  resembles 
its  reflection  in  a  mirror.  If  such  molecules  be  represented 
as  mirror  images  (Fig.  8  and  Fig.  9)  it  will  be  seen  that  on 
turning  one  so  that  the  a  and  b  in  both  figures  coincide, 
the  c  and  d  of  one  will  not  coincide  with  c  and  d  of  the 
other.  If  now  Figure  8  rotates  the  plane  of  polarized 
light  to  the  right,  Figure  £  will  rotate  it  to  the  left  be- 
cause of  its  opposite  handed  structure.  This  isomerism  in 
space  is  termed  stereochemical  isomerism  or  stereoisomerism. 


The  Alcohols  35 

For  simplicity  the  formulae  of  asymmetric  compounds 
are  written  as  if  all  the  atoms  or  groups  lie  in  the  same 
plane.  The  belief  that  the  atoms  and  groups  in  the  com- 
pounds under  discussion  do  not  lie  in  the  same  plane  is 
supported  by  the  fact  that  compounds  containing  but 
two  dissimilar  groups,  as  C  aabb,  do  not  exist  in  two  iso- 
meric  forms.  If  all  were  in  the  same  plane  two  arrange- 
ments, like  Figure  10,  would  be  possible,  which  must  lead 
to  different  physical  properties  because  in  the  one  case 
like  groups  are  separated  by  unlike  ones,  while  in  the  other 
like  groups  are  adjacent  to  one  another.  No  isomers  of 
this  type  have  ever  been  observed,  although  there  are 
known  a  large  number  of  compounds  of  the  general  for- 
mula CaJ)2. 

a  a 

a — C — b  6' — C — b 

b  FIG.  10.         a 

The  third  isomer  of  this  amyl  alcohol  is  a  mixture  of 
equal  numbers  of  molecules  of  the  right-and  left-handed 
varieties.  The  influence  of  one-half  of  the  molecules  in 
rotating  the  plane  of  polarized  light  in  one  direction  is 
exactly  counteracted  by  the  opposite  rotating  power  of 
the  other  half,  with  the  result  that  it  appears  to  be 
without  optical  activity.  When  an  excess  of  one  optical 
form  exists  in  a  mixture  of  the  two  optically  active  vari- 
eties, this  part  exerts  its  effect  and  the  mixture  becomes 
optically  active  in  proportion  to  the  excess  of  one  variety 
over  the  other. 


36     Organic  Chemistry  for  Students  of  Medicine 

This  type  of  isomerism  is  of  great  significance  in  biology, 
since  with  but  few  exceptions  the  organic  compounds  which 
play  important  roles  in  the  life  processes  of  plants  and 
animals  possess  this  type  of  asymmetry. 

21.  The  Higher  Alcohols.  —  One  of  the  higher  homo- 
logues  of  methyl  alcohol  which  should  be  mentioned,  is 
normal  hexyl  alcohol,  CH3— (CH2)4— CH2OH  (B.  P.  157°) 
which  occurs  in  the  oil  of  the  seeds  of  Heracleum  gigan- 
teum,  in  the  oil  of  the  fruit  of  several  plants,  and  in  slight 
amount  in  fusel  oil.  The  following  are  also  biologically 
important : 

Normal  heptyl  alcohol  CH3—  (CH2)5— CH2OH  B.  P.  176° 

Normal  octyl  alcohol  CH3—  (CH2)6— CH2OH  B.  P.  196° 

Nonyl  alcohol  CH3—  (CH2)7— CH2OH  B.  P.  213° 

Dodecyl  alcohol  CH3—  (CH2)10— CH2OH  M.  P.  24-26° 

Cetyl  alcohol  CH3—  (CH2)14— CH2OH  M.  P.  49° 

Octadecyl  alcohol  CH3—  (CH2)16— CH2OH  M.  P.  59° 

Carnaubyl  alcohol  CH3— (CH,)^— CH2OH  M.  P.  68° 

Ceryl  alcohol  CaeHsaOH 

Myricyl  alcohol  C30H6iOH 

The  higher  alcohols,  Cg  to  Cis,  are  found  in  various  plant 
oils  in  small  amounts  usually  combined  with  organic  acids, 
as  esters  (28).  Cetyl  alcohol  occurs  as  a  constituent  of 
spermaceti,  an  animal  wax  derived  from  the  sperm  whale, 
and  in  the  oil  secreted  by  water  birds  for  lubricating  their 
feathers. 

Ceryl  alcohol  is  an  important  constitutent  of  many 
waxes,  as  Chinese  wax,  beeswax,  etc. 

Myricyl  alcohol  is  likewise  a  very  common  constituent 
of  waxes.  (See  waxes,  95.) 


The  Alcohols  37 

22.  The  Diatomic  Alcohols.  —  It  has  been  found  im- 
possible to  prepare  in  the  isolated  state  compounds  of  the 

R,         OH  .OR 

type      /C\          such  as  H2C\          f°r  the  reason  that 

W        X)H  \)H 

they  are  unstable  and  as  soon  as  formed  they  separate  a 
molecule  of  water  with  the  formation  of  a  new  class  of 
compounds,  the  aldehydes.  These  will  be  treated  more 
fully  later  (30). 

There  are,  however,  many  examples  of  compounds  which 
contain  more  than  one  alcohol  radical.  The  simplest 

CH2OH 
of  these  is  ethylene  glycol  or  glycol    \  •     It  is  formed 

CH2OH 

in  a  manner  analogous  to  monatomic  alcohols,  viz.,  by  the 
action  of  water  or  metallic  hydroxides  on  ethylene  halogen 
derivatives  (6).  Ethylene  chloride  is  too  stable  to  react 
with  water  directly  even  under  pressure,  but  ethylene 
bromide  will  react  when  heated  in  a  sealed  tube  with 
water,  forming  glycol  and  hydrobromic  acid : 

CH2Br    HOH     CH2OH 

|  +  =|  +2HBr. 

CH2Br    HOH     CH2OH 

Glycol  is  a  colorless  liquid,  readily  soluble  in  water, 
and  has  a  sweet  taste.  It  boils  without  decomposition 
at  197°  and  solidifies  in  a  freezing  mixture.  Its  melting 
point  is  —  11.5°  and  its  specific  gravity  at  0°  is  1.125,  water 
being  1.000.  It  is  therefore  heavier,  volume  for  volume, 
than  any  of  the  monatomic  alcohols,  which  are  all  lighter 
than  water. 


38    Organic  Chemistry  for  Students  of  Medicine 

Glycol  does  not  occur  in  nature  in  the  free  state,  but  is 
a  constituent  of  a  very  important  class  of  compounds  of 
complex  structure,  the  lecithins  (96).  Moreover  it  is  of 
great  theoretical  interest,  since  it  probably  occurs  as  an 
intermediary  product  in  the  degradation  of  certain  food- 
stuffs in  the  processes  of  metabolism  (48). 

Glycol  reacts  with  alkali  metals,  as  do  the  monatomic 
alcohols,  forming  e.g.  sodium,  or  potassium  glycollate,  and 
hydrogen : 

CH2OH  CH2ONa 

|  +2Na=    |  +H2 

CH2OH  CH2ONa 

With  fuming  nitric  acid  it  reacts  to  form  glycol  dinitrate  : 

CH2OH     HNO3     CH2NO3 
|  +  =|  +2H20 

CH2OH   .HN03     CH2NO3 

Glycol  chlorhydrin,  CH2OH — CH2C1,  is  obtained  by 
passing  hydrochloric  acid  gas  into  warm  glycol  (25). 
It  is  a  liquid,  soluble  in  water,  and  boiling  at  130°. 

CH2— CH2 

23.   Ethylene  Oxide.  —    \     /     .    Glycol  does  not 


form  an  anhydride  on  treating  it  with  reagents  which 
abstract  water.  From  glycol  chlorhydrin,  by  abstracting 
a  molecule  of  HC1  by  treatment  with  alkalies,  there  results 
ethylene  oxide.  This  compound  is  a  gas,  since  it  boils  at 
14°.  It  readily  takes  up  water,  forming  glycol : 

CH2\  H       CH2OH 

I        >  +       =| 
CH2/          OH     CH2OH. 


The  Alcohols  39 

It  also  readily  adds  hydrochloric  acid,  forming  glycol 

CH2\  H      CH2OH 

chlorhydrin:        |         )>O+        =  |. 

CH2/  Cl      CH2C1. 

24.  From  propane  two  glycols  are  derived :    Alpha  or 
a-propylene  glycol  CH3  -  CHOH  -CH2OH,  in  which  one 
hydroxyl  group  is  attached  to  the  middle  carbon  atom  and 
therefore  in  the  alpha  position  to  the  end  carbon  atoms, 
and  Beta  or  /3-propylene  glycol,  in  which  each  hydroxyl  is 
bound  to  an  end  carbon  atom  and  is  therefore  in  the  /3- 
position  to  the  other. 

25.  Triatomic  Alcohols.  —  Glycerol,  commonly  called 
glycerine,  a  name  which  it  received  before  the  modern 
system  of  chemical  nomenclature  was  developed,  is  a 
derivative  of  propane,  from  which  it  is  formed  by  the  sub- 
stitution of  three  hydroxyl  groups  for  three  hydrogen  atoms. 
It  is  a  never-failing  constituent  of  all  fats,  where  it  occurs 
in  combination  with  the  fatty  acids.     It  has  been  prepared 
synthetically  from  triiodo-propane  by  the  action  of  water : 

CH2I  CH2OH 

CHI  +  3HOH  =  CHOH  +  SHI 

CH2I  CH2OH 

Glycerol  reacts  with  phosphorus  triiodide,  Pis,  to  form 
the  triiodo  propane,  this  being  also  called  triiodo-hydrin. 

Glycerol  is  a  colorless,  odorless,  oily  liquid  of  sweet 
taste.  It  has  a  strong  affinity  for  water,  and  takes  up 
moisture  from  the  air.  It  is  soluble  in  water  and  in  alcohol 
in  all  proportions,  but  very  nearly  insoluble  in  ether.  On 


40    Organic  Chemistry  for  Students  of  Medicine 

long  standing  at  low  temperatures  it  solidifies,  and  the  crys- 
tals thus  formed  do  not  melt  below  17°.  It  boils  at  290° 
but  undergoes  some  decomposition.  Under  reduced  pres- 
sure it  can  be  distilled  without  decomposition.  At  12  mm. 
it  distills  at  170°.  It  is  slowly  volatile  with  water  vapor. 
Its  specific  gravity  at  15°  is  1.265.  Its  chemical  behavior 
is  in  accord  with  the  theory  that  it  is  a  triatomic  alcohol. 
Thus  when  glycerol  is  slowly  dropped  into  a  mixture  of 
concentrated  sulphuric  acid  and  fuming  nitric  acid  trinitro- 
glycerol,  usually  called  nitroglycerine,  is  formed.  The  sul- 
phuric acid  facilitates  the  reaction  by  its  affinity  for  water, 
which  it  withdraws  from  the  system  as  soon  as  formed : 

CH2OH  CH2NO3 

I  I 

CHOH  +  3  HNO3  =  CHN03  +  3H2O 

CH2OH  CH2N03 

Nitroglycerine 

Nitroglycerine  is  a  heavy  colorless  oil  when  pure,  but 
usually  has  a  yellow  color.  It  is  sweet  to  the  taste  and  is 
extremely  poisonous,  acting  chiefly  on  the  central  nervous 
system.  It  is  employed  in  medicine  for  its  action  on  the 
heart  and  is  directly  injected  into  the  blood  as  a  remedy 
in  case  of  carbon  monoxide  poisoning.  When  heated  to 
180°  it  explodes.  Its  explosion  can  be  induced  by  a  sharp 
blow.  The  principal  use  of  nitroglycerine  is  as  an  explo- 
sive. When  absorbed  by  certain  porous  substances,  as 
sawdust,  clay,  wood  pulp,  etc.,  it  forms  dynamite.  Mixed 
with  nitrocellulose,  vaseline,  and  acetone,  it  forms  the 
smokeless  powder  called  cordite. 


The  Alcohols  41 

Glycerol,  like  other  compounds  containing  several 
hydroxyl  groups,  dissolves  alkalies  and  oxides  of  the  heavy 
metals,  forming  compounds  analogous  to  the  alcoholates. 
The  hydrogen  atoms  of  the  OH  groups  are  in  these  replaced 
by  the  metal.  The  structure  of  such  compounds  may  be 
illustrated  by  the  following  formula  : 

CH2OH  CH2O 

i  > 

CHOH  +  Cu(OH)2  =  CHO  +  2H2O 

CH2OH  CH2OH 

With  basic  lead  acetate  and  ammonia  glycerol  forms  an 
insoluble  lead  glycerate. 

When  heated  with  hydrochloric  acid,  glycerol  reacts 
with  the  formation  of  water  and  the  replacement  of  one  or 
two  hydroxyl  groups  by  chlorine  : 

CH2OH  CH2C1 

I  I 

CHOH  +  HC1  =  CHOH  +  H2O 

I  I 

CH2OH  CH2OH 

Monochlorhydrin 

CH2C1  CH2C1 

I  I 

CHOH  +  HC1  =  CHOH  +  H2O 

I  I 

CH2OH  CH2C1 

Dichlorhydrin 

This  reaction  cannot  be  effected  by  the  use  of  hydriodic 
acid,  since  the  latter  acts  as  a  strong  reducing  agent,  owing 


42    Organic  Chemistry  for  Students  of  Medicine 

to  the  great  tendency  it  shows  to  separate  free  iodine,  thus 
making  available  nascent  hydrogen  for  the  abstraction  of 
oxygen.  Thus  on  heating  glycerol  with  five  molecular 
equivalents  of  hydriodic  acid,  isopropyl  iodide  is  produced  : 

CH2OH 


CHOH  +  5  HI  =  CHI  +  3  H20  +  4  1 

I  I 

CH2OH  CH3 

Isopropyliodide 

Under  carefully  regulated  conditions  this  reaction  is 
nearly  quantitative,  and  on  the  measurement  of  the  iodine 
in  the  isopropyl  iodide  produced  from  a  sample  depends  the 
quantitative  estimation  of  glycerol  proposed  by  Zeisel  and 
Fanto. 

Glycerol  is  readily  oxidized,  i.e.  it  exerts  a  reducing  ac- 
tion (abstraction  of  oxygen)  on  Fehling's  solution  even  in 
the  cold,  owing  to  its  conversion  into  glyceraldehyde  (36). 

26.  Erythritol  or  Erythrite, 

CH2OH—  (CHOH)2—  CH2OH, 
exists  in  nature  in  certain  algae. 

27.  The  Sulphur  Alcohols.     Mercaptans.  —  Just  as  the 
alcohols  are  derivatives  of  water,  formed  by  replacing  one 
of  the  hydrogen  atoms  by  an  alkyl  group,  so  also  there 
exists  a  class  of  compounds  of  analogous  constitution 
derived  from  hydrogen  sulphide.     These  are  known  as 
thio-alcohols,  mercaptans,  or  alkyl  sulph-hydrates  : 

H—  O—  H        R-0—  H        H—  S—  H        R—  S—  H 

Water  Alcohol  Hydrogen  Mercaptan 

sulphide 


The  Alcohols  43 

They  are  formed  by  warming  alkyl  halides  with  potas- 
sium sulph-hydrate  in  concentrated  aqueous  or  alcoholic 
solution : 

C2H6I  +  KSH  =  C2H5SH  +  KI 

Mercaptan 

Methyl  mercaptan,  CH3SH,  is  a  gas,  B.  P.  6°.  It  is 
produced  by  the  action  of  anaerobic  bacteria  on  proteins, 
being  one  of  the  products  of  putrefaction.  It  has  a  dis- 
gusting odor.  It  is  a  constituent  of  intestinal  gases. 

Ethyl  mercaptan,  CH3 — CH2SH,  is  a  liquid  with  an 
extremely  obnoxious  odor ;  B.  P.  36°.  It  reacts  with  so- 
dium, forming  C2H5SNa,  analogous  to  sodium  alcoholate. 


CHAPTER  III 
ESTERS  AND  ETHERS 

28.  Esters.  —  When  alcohols  are  treated  with  acids 
which  have  a  strong  affinity  for  water,  a  reaction  may  take 
place  in  which  a  molecule  of  water  and  a  new  compound 
called  an  ester  are  produced.  Thus  the  action  of  hydri- 
odic  acid  on  alcohol  with  the  production  of  an  alkyl 
halide  (20)  is  representative  of  a  general  type  of  reac- 
tion. Thus : 

(a)  CH3— CH2OH  +  H(X  CH3— CH2— (X 

>S02=  >S02 

HCK  HCK 

Alcohol  Sulphuric  Ethyl  sulphuric  acid 

acid 

Compounds  of  the  type  of  ethyl  sulphuric  acid  are 
known  as  ethereal  acids. 

(6)     2  C2H5OH  +  H2S04  =  CH3— CH2— (X 

>SO2+2H20 
CH3— CH2— O/ 

Diethyl  sulphate 

Diethyl  sulphate  is  a  neutral  ester. 
These  compounds  can  also  be  formed  by  the  action  of  the 
silver  salts  of  the  acids  on  the  alkyl  iodides : 

yOAg    ICH3    CH3(X 
SO/         +          =  NSO,  +  2  Agl 

X)Ag    ICH3    CH3(X 

Silver  sulphate        Methyl  Dimethyl 

iodide  sulphate 

44 


Esters  and  Ethers  45 

Diethyl  sulphate  is  a  colorless  oily  liquid  possessing  a 
peppermint  odor.  It  is  insoluble  in  water.  It  boils  at 
208°.  It  is  readily  hydrolysed,  i.e.  broken  up  with  the 
entrance  of  water  into  the  compound,  but  the  original 
substances,  alcohol  and  sulphuric  acid,  from  which  it  was 
formed,  are  not  regenerated.  Instead  oliethyl  ether  is 
produced  (29). 

(c) 

CHa— CH2\-(X 

\  >S02+HOH  =  C2H6— O— C2H5+H2S04 

CH3— CH2— OK  Ethyl  ether 

The  structure  of  diethyl  sulphate  is  also  shown  by  its 
formation  from  alcohol  and  sulphuryl  chloride, 

HOC2H5  /OC2H6 

=SO2<  +2H 

HOC2H5  X)C2H6 


(d)  Ethyl  Sulphuric  Acid  is  a  strongly  acid  liquid  of 
an  oily  character  and  possesses  no  odor.  It  is  soluble  in 
water  in  all  proportions.  It  is  obtained  by  mixing  alcohol 
with  strong  sulphuric  acid.  The  calcium  and  barium  salts 
are  soluble  while  barium  sulphate  is  insoluble.  The 
solution  containing  ethyl  sulphuric  acid,  alcohol,  and  sul- 
phuric acid  is  neutralized  with  BaCOs  and  the  BaSO4 
filtered  off.  On  adding  just  enough  sulphuric  acid  to 
combine  with  the  barium  in  the  filtrate  the  barium  is 
removed  and  free  ethyl  sulphuric  acid  is  left  in  solution. 
It  is  not  very  stable,  decomposing  slowly  into  alcohol 
and  sulphuric  acid  in  the  presence  of  water  at  ordinary 
temperatures  and  quickly  on  boiling.  Potassium  ethyl 


46     Organic  Chemistry  for  Students  of  Medicine 

sulphate  is  very  stable  and  can  be  recrystallized  from  boil- 
ing alcohol. 

When  ethyl  sulphuric  acid  is  heated  it  forms  the  neutral 
ester  diethyl  sulphate  and  free  sulphuric  acid  : 


xOC2H5       HOV  /OH    C2H5(X 

2<  +  >S02=S02<        +  >S02 

X)H       CaHfiCK  \OH    C2H5CK 


(e)  Esters  of  Sulphurous  Acid.  —  When  alkyl  iodides 
react  with  sodium  sulphite  there  is  formed  the  sodium  salt 
of  ethyl  sulphonic  acid  : 

C2H6I  +  NasS03  =  C2H5S03Na  +  Nal 


The  free  acid  C2H6SO3H  is  a  very  stable  strong  mono- 
basic acid  easily  soluble  in  water.  It  is  not  saponified 
even  by  boiling  with  water  or  alkalies.  Even  boiling 
concentrated  nitric  acid  does  not  act  upon  it,  nor  does  free 
chlorine,  but  fused  potassium  hydroxide  decomposes  it, 
regenerating  alcohol  and  forming  potassium  sulphite. 

The  same  compound  is  formed  by  the  oxidation  of 
mercaptan  with  nitric  acid  or  potassium  permanganate  : 


H(X 
0=          > 


C2H6SH  +  3 

C2H5 

That  this  acid  contains  a  hydroxyl  group  is  shown  by  its 
yielding  with  PC15  an  acid  chloride  which  decomposes 
with  water,  regenerating  the  acid.  The  method  of  forma- 
tion also  shows  that  the  sulphur  is  linked  directly  to  carbon. 

By  the  action  of  alkyl  iodide  on  silver  sulphite  sulphonic 
ethers  are  formed. 


Esters  and  Ethers  47 

2  CH3— CH2I  +  Ag2S03  =  (C2H5)2SO3  +  2  Agl 


Ethyl  sulphonic 
ethyl  ether 

This  is  so  stable  that  it  is  difficultly  saponifiable.  B .  P.  21 3°. 
(/)  Ethers  of  Sulphurous  Acid.  —  When  alcohol  reacts 
with  sulphuryl  chloride  there  is  formed  a  compound 
which  is  isomeric  with  ethyl  sulphonic  ethyl  ether,  but 
has  entirely  different  properties  : 

xCl    HOC2H5 
S0<(      +  =(C2H5)2S03  +  2HC1 

XC1       HOC2H5       Diethyl  sulphite 

Diethyl  sulphite  is  rapidly  saponified  by  water.     On 
careful  partial  saponification  the  unstable  potassium  salt 


25v 

of  ethyl  sulphurous  acid  /SO3  is  formed.     The  free 

W 

acid  which  is  isomeric  with  ethyl  sulphonic  acid  is  incap- 
able of  existence,  decomposing  at  once  into  its  components. 
The  stable  ethyl  sulphonic  acid,  being  known  to  have  its 
sulphur  directly  linked  to  carbon  and  to  contain  one 
hydroxyl  group,  is  assigned  the  structure : 

C2H5         O 

\  ^      and  the  isomeric  ethyl     C2H5 — (X 
S          sulphurous  acid  the  /S=O 

HO  O     follOWmS:  Ethyl  anurous  acid 


Ethyl  sulphonic 
acid 


(g)   Ethyl  alcohol  reacts  with  nitric  acid  HONOiz  to 
produce  ethyl  nitrate : 

CH3— CH2OH  +  HON02  =  C2H5ONO2  +  H2O 


48    Organic  Chemistry  for  Students  of  Medicine 

It  is  a  liquid  which  boils  at  66°.  It  has  a  pleasant  odor. 
It  is  soluble  in  water 

Ethyl  nitrate,  CH3 — CH2O — NQj,  is  produced  directly 
from  its  components  and  resembles  methyl  nitrate.  It 
boils  at  86°,  has  a  sweet  taste,  but  a  bitter  after  taste. 
It  is  soluble  in  alcohol  and  ether. 

Both  of  these  substances  are  explosive  when  heated 
quickly. 

Amyl  nitrate,  C5HnONO2,  is  prepared  in  an  analogous 
manner.  It  is  a  colorless  liquid  which  boils  at  148°. 

(h)  Two  esters  of  nitrous  acid  are  important  because 
of  their  pharmacological  properties.  They  are  ethyl  nitrite, 
which  is  frequently  called  nitrous  ether.  It  is  a  gas  which 
boils  at  -  12°. 

C2H5OH  +  HONO  =  C2H5ONO 

Nitrous  acid         Ethyl  nitrite 

It  is  employed  in  solution  in  ethyl  alcohol  (15%). 

Amyl  nitrite  boils  at  99°.  Its  physiological  action  is 
distinct  from  that  of  amyl  nitrate. 

29.  Ethers.  —  Just  as  a  molecule  of  alcohol  and  one 
of  an  acid  can  be  condensed  with  the  formation  of  one  of 
an  ester  and  one  of  water,  so  two  molecules  of  alcohol  can 
be  condensed  with  the  loss  of  water  to  form  an  ether : 

(a)  Alcohol  +  Acid  =  Ester  +  Water 

(6)  CH3|QH  +  H|OCH3  =  CH3— O— CH3 

Methyl  ether 

The  formation  of  ethyl  ether,  which  is  the  most  common 
one  and  is  usually  referred  to  as  ether,  has  been  described 
in  connection  with  the  hydrolysis  of  the  ester  diethyl  sul- 


Esters  and  Ethers  49 

phate  (28  c.).  In  practice  it  is  prepared  by  dropping  alco- 
hol continuously  into  a  solution  of  ethyl  sulphuric  acid 
heated  to  140-145°  C. 

C2H5— Ox 

^>S02  +  H2O  =  C2H5— O— C2H5  +  H2SO4 

C2H5— O7 

HOX  C2H50X 

2  C2H5OH  +         ^SO,  =  \Sa  +  H2O 

HC/  C2H5CK 

Diethyl  sulphate  is  alternately  formed  and  decomposed 
and  the  ether  distills  over,  together  with  some  alcohol  and 
SO2.  From  this  it  would  appear  that  since  the  sulphuric 
acid  is  constantly  being  regenerated  it  should  act  over  and 
over  again  so  that  a  small  amount  should  induce  the  forma- 
tion of  ether  indefinitely.  This  is  not  the  case,  for  the 
following  reason:  With  the  formation  of  each  molecule 
of  ether  there  is  likewise  produced  a  molecule  of  water. 
Now  ethyl  sulphuric  acid  is  readily  hydrolyzed  to  alcohol 
and  sulphuric  acid  in  the  presence  of  water,  and  in  any 
solution  containing  these  three  substances  there  will  be 
established  a  state  of  equilibrium  in  which  there  will  exist 
a  definite  relationship  between  the  amount  of  alcohol, 
ethyl  sulphuric  acid,  sulphuric  acid,  and  water.  Increas- 
ing the  concentration  of  alcohol  will  cause  the  formation 
of  more  ethyl  sulphuric  acid,  while  adding  water  causes 
the  saponification  of  some  of  the  ethyl  sulphuric  acid  into 
its  components.  The  water  which  is  produced  in  the  for- 
mation of  ether  distills  over  to  some  extent,  but  a  part 


50     Organic  Chemistry  for  Students  of  Medicine 

remains  behind  in  the  still.  This  tends  therefore  to  cause 
a  progressive  decrease  in  the  amount  of  ethyl  sulphuric 
acid  in  the  flask,  so  that  after  a  time  little  or  no  ether  is 
formed.  Instead  the  alcohol  distills  over  as  fast  as  added. 
The  latter  is  removed  from  the  distillate  by  neutralizing 
the  H2SOs  with  milk  of  lime.  The  alcohol  passes  princi- 
pally into  the  water  layer,  and  the  ether,  which  is  sepa- 
rated from  the  water  layer  in  a  separatory  funnel,  is  again 
distilled. 

The  last  traces  of  water  and  alcohol  are  removed  from 
ether  by  placing  in  it  granulated  calcium  chloride,  which 
has  a  strong  affinity  for  both  these  substances. 

Ethyl  ether  boils  at  34.97°.  It  has  an  agreeable  odor. 
Prolonged  breathing  of  it  causes  loss  of  consciousness. 
It  is  much  employed  in  surgery  as  an  anaesthetic.  One 
volume  dissolves  in  11.1  volumes  of  water  at  25°,  and 
ether  dissolves  water  to  the  extent  of  about  a  2% 
solution  by  volume  at  12°.  It  is  much  less  soluble  in  a 
saturated  salt  solution.  With  air  ether  vapors  produce 
highly  explosive  mixtures.  Great  care  should  be  exer- 
cised therefore  in  handling  ether  wherever  there  is  a 
possibility  of  ignition,  as  during  distillation.  It  is  best 
to  place  the  distillation  flask  in  hot  water  and  to  dis- 
pense with  a  flame.  A  small  flask  should  be  employed 
and  fresh  portions  of  ether  added  from  time  to  time, 
as  the  distillation  proceeds.  Small  receivers  frequently 
emptied  are  preferable  to  one  large  one. 

Ether  dissolves  a  great  variety  of  chemical  substances 
and  is  indispensable  as  a  solvent  in  chemical  work.  In 
many  instances  substances  can  be  separated  from  complex 


Esters  and  Ethers  51 

mixtures  by  extracting  a  water  solution  with  ether.  This 
depends  upon  the  fact  that  when  a  substance  is  soluble 
in  two  liquids  which  do  not  mix,  as  ether  and  water,  it 
will,  when  water  and  ether  are  shaken  together  and  then 
allowed  to  separate  into  two  layers,  distribute  itself 
between  the  ether  and  the  water.  If  now  the  ether  be 
separated  from  the  water  by  means  of  a  separatory  funnel, 
and  fresh  ether  shaken  with  the  water,  a  division  of  the 
dissolved  substance  will  again  take  place.  In  this  manner 
by  shaking  repeatedly  with  fresh  portions  of  ether  the 
water  solution  becomes  progressively  poorer  in  the  dis- 
solved substance.  The  ether  on  evaporation  leaves  behind 
the  material  which  it  contained. 

The  constitution  of  the  ethers  is  further  shown  by  their 
formation  from  an  alcoholate  and  an  alkyl  halide : 


C2H50  Na  +I|C2H5  =  C2H5— O— C2H5  +  Nal 


Sodium  ethylate 

This  reaction  serves  to  show  what  actually  happens 
when  sodium  reacts  with  an  alcohol  (15).  There  are  two 
possibilities.  The  sodium  might  replace  one  of  the  hydro- 
gen atoms  which  is  linked  with  carbon,  or  that  one  which  is 
linked  to  oxygen.  If  the  former  were  true,  we  should  have 
formed  a  compound  of  the  following  structure : 

CH3— OH  +  Na  =  NaCH2OH 

On  causing  this  to  react  with  an  alkyl  iodide  there 
should  be  formed  a  higher  alcohol: 

CH3I  +  NaCH2— OH  =  CH3— CH2— OH  +  Nal 


52     Organic  Chemistry  for  Students  of  Medicine 

The  formation  of  ethers  in  this  way  proves  that  in  these 
the  two  alkyl  groups  are  linked  together  through  oxygen. 
This  is  called  Williamson's  reaction,  after  the  name  of  its 
discoverer. 

If  to  the  mixture  of  alcohol  and  sulphuric  acid  (contain- 
ing ethyl  sulphuric  acid)  there  is  added,  beginning  just 
before  distillation  commences,  an  alcohol  other  than  ethyl 
alcohol,  a  mixed  ether  will  result.  In  this  way  numerous 
ethers  containing  different  alkyl  radicals  can  be  produced. 

C2H5- 

[n+H2SO4 


Amyl  alcohol  Ethyl  amyl  ether 

H 

This  furnishes  further  evidence  that  the  steps  in  the 
formation  of  ether  are  as  described  above. 


CHAPTER  IV 
THE   ALDEHYDES  AND  KETONES 

30.  Oxidation  Products  of  the  Alcohols.  —  It  has  long 
been  known  that  alcohol-containing  solutions,  as  fer- 
mented cider,  wine,  or  beer,  soon  become  sour  when 
exposed  to  the  air  in  open  vessels  at  room  temperature. 
Vinegar  is  formed  through  the  change  of  alcohol  into 
acetic  acid.  In  the  absence  of  oxygen  this  change  does 
not  take  place,  and  it  is  greatly  accelerated  by  thorough 
aeration  of  the  solution,  as  by  causing  it  to  pass  through 
porous  material.  The  oxidation  is  not  spontaneous,  but 
results  from  the  growth  in  the  solutions  of  a  microorganism 
Mycoderma  aceti,  or  "  mother  of  vinegar."  If  the  vessel 
containing  the  alcoholic  solution  which  is  undergoing  this 
change  admits  but  an  inadequate  supply  of  air  (oxygen) 
there  accumulates  an  intermediary  product  known  as 
aldehyde  or,  from  its  relation  to  acetic  acid,  acetaldehyde. 

The  change  which  takes  place  in  these  processes  is 
shown  by  the  following  equations: 

CH3— CH2OH  +  O  =  CH3— CHO  +  H2O 

Acetaldehyde 

CH3— CHO  +  O  =  CH3— COOH 

Acetic  acid 

Oxygen  of  the  air  (molecular  oxygen)  cannot  effect  this 
oxidation,  except  through  the  agency  of  an  "  oxygen 
carrier,"  or  catalyzer,  which  "  activates  "  it.  This  action 

53 


54     Organic  Chemistry  for  Students  of  Medicine 

is  brought  about  by  the  presence  in  the  acetic  acid  organ- 
ism of  oxydases. 

Numerous  examples  are  known  of  the  activation  of 
molecular  oxygen  through  the  agency  of  inorganic  cata- 
lyzers. Thus  a  mixture  of  hydrogen  and  air  is  stable  at 
ordinary  temperatures  and  can  be  left  for  a  long  period 
without  the  -hydrogen  and  oxygen  combining  to  form 
water.  If  a  platinum  spiral  be  introduced  into  such  a 
mixture,  the  volume  of  the  gas  mixture  will  decrease 
noticeably  and  the  platinum  grow  warm.  The  hydrogen 
and  oxygen  will  now  rapidly  combine.  If  instead  of  a 
platinum  spiral  very  finely  divided  metal,  platinum  sponge, 
be  employed,  the  two  elements  may  combine  with  explo- 
sive violence. 

Another  example  of  the  effect  of  an  inorganic  catalyzer 
is  seen  in  the  technical  process  of  converting  methyl  alcohol 
into  formaldehyde.  Air  and  methyl  alcohol  in  the  proper 
proportions  to  supply  oxygen  for  the  oxidation  of  the  alco- 
hol form  a  relatively  stable  mixture.  It  can  be  heated  to 
a  relatively  high  temperature  without  any  oxidation  taking 
place.  If  however  a  copper  gauze  which  has  been  oxi- 
dized on  its  surface  be  warmed  gently  and  the  air-alcohol 
mixture  passed  slowly  over  it,  the  oxidation  of  the  alcohol 
is  rapidly  effected,  water  and  formaldehyde  being  formed. 
The  heat  generated  by  the  oxidation  serves  to  keep  the 
copper  in  a  glowing  condition : 

CH3OH  +  0  =  HCHO  +  H2O 

Formaldehyde 

The  exact  nature  of  the  process  by  which  these  accelera- 
tions of  reactions  is  brought  about  is  not  known  with  cer- 


The  Aldehydes  and  Ketones  55 

tainty.  The  amount  of  acceleration  depends  upon  the 
amount  of  surface  of  metal  or  oxide  exposed  to  the  react- 
ing mixture,  and  it  is  known  that  platinum  can  absorb 
relatively  large  amounts  of  certain  gases,  and  the  more  the 
greater  the  degree  of  fineness  of  its  division.  Since  the 
more  finely  divided  the  metal  the  greater  the  surface  ex- 
posed, the  reason  for  the  higher  efficiency  of  the  metal  in 
a  fine  state  of  division  becomes  apparent.  The  catalytic 
action  is  most  simply  explained  by  assuming  that  the  gases 
dissolve  in  the  surface  layer  of  the  metal  and  therefore  exist 
in  much  more  concentrated  state  by  which  more  molecules 
are  brought  together  for  interaction  in  a  given  time. 

For  the  preparation  of  acetaldehyde,  which  is  for  brev- 
ity ordinarily  referred  to  as  aldehyde,  in  the  laboratory 
the  oxidation  of  alcohol  is  effected  by  chromic  acid : 

3  C2H5OH  +  2  K2Cr04  +  5  H2SO4 

=  3  CH3— CHO  +  Cr2(S04)3  +  2  K2SO4  +  8  H2O. 

Aldehyde 

In  this  reaction  the  sulphuric  acid  first  reacts  with  the 
potassium  chromate,  forming  chromic  acid  : 

OH 


K2CrO4  +  H2SO4  =  K2SO4 

\) 
OH 

The  chromium  in  the  chromic  acid  gives  up  its  oxygen 
to  the  alcohol,  passing  from  the  hexavalent  to  the  trivalent 
state. 

The  green  color  of  the  chromous  sulphate  and  the  fruity 
odor  of  the  aldehyde  are  so  characteristic  that  this  reaction 


56     Organic  Chemistry  for  Students  of  Medicine 

is  employed  reversably  as  a  qualitative  test  for  both 
chromic  acid  and  for  alcohol. 

When  chlorine  is  passed  into  a  primary  or  secondary 
alcohol,  hydrogen  is  replaced  by  chlorine,  in  a  manner 
analogous  to  the  behavior  of  hydrocarbons.  The  chlorine 
atom  always  replaces  a  hydrogen  attached  to  the  carbon 
atom  which  holds  the  hydroxyl  group,  i.e.  to  the  carbon 
atom  already  linked  to  a  negative  group.  The  two  nega- 
tive groups  cannot  remain  attached  in  this  way,  so  the 
chlorinated  alcohol  has  but  a  transitory  existence.  There 
results  at  once  a  separation  of  HC1  and  the  formation  of 
an  aldehyde ; 

CH3— CH2OH  +  C12  =  CH3— CHC1-OH  +  HC1 
CHa— CHC1— OH  — >-  CH3— CHO  +  HC1 

31.   Constitution  of  the  Aldehydes  and  Acids.  —  The 

relationship  between  the  primary  alcohols  and  their 
oxidation  products,  the  aldehydes  and  acids,  is  shown  by 
the  following  consideration :  The  primary  alcohols  cor- 
respond to  the  general  formula  CnH2n+2O ;  the  aldehydes 
to  the  formula  CnH2nO,  due  to  the  loss  of  two  hydrogen 
atoms  through  the  first  stage  of  oxidation;  while  the  acids 
which  result  from  the  oxidation  of  the  aldehydes  cor- 
respond to  the  general  formula  CnH2n02. 

The  constitutional  formulae  assigned  to  these  three 
classes  of  compounds  are  as  follows : 

R  R  R  R  R 

I/H          I/H|  |  | 

C— H  C        or  CHO  C— OH  or  CO  -  OH 

\OH  \O  \O 

Alcohol  Aldehyde  Acid  • 


The  Aldehydes  and  Ketones  57 

The  primary  alcohols,  the  aldehydes  and  corresponding 
acids  are  derived  from  the  hydrocarbons  by  the  substitu- 
tion of  a  hydrogen  atom  linked  to  a  primary  carbon  atom 
by  the  following  groups :  Q 

I  I  // 

— C— OH  C=O  — C 

.1  I  \ 

Carbinol  group  Carbonyl  OTT 

(Alcohol)  group 

(Aldehyde  Carboxyl  group 
or  Ketone)  (Acid) 

The  behavior  of  these  groups  when  acted  upon  by  PC15 
throws  further  light  upon  their  structure.  Thus  the  alco- 
hols yield,  as  already  pointed  out,  alkyl  halides,  the  OH 
acting  as  a  unit  and  being  replaced  by  Cl,  a  monovalent 
element.  When  PCU  acts  upon  aldehydes,  the  oxygen 
is  replaced  by  two  Cl  atoms  forming  dichlor  hydrocarbons. 
With  the  organic  acids  PCI 5  replaces  the  OH  group  as  in 
the  alcohols  and  leads  to  the  formation  of  acid  chlorides : 

OH  +  PC15  =  CH3— CH2C1  +  POC13  +  HC1 

Ethyl  chloride 

+  PC15  =  CH3— CHC12  +  POCk 

Ethylidene  chloride 

CHs— COOH  +  PC15  =  CH3— COC1  +  POC13  +HC1 

Acetyl  chloride 

32.  Properties  of  the  Aldehydes.  —  (1)  The  aldehydes 
are  characterized  by  exceptional  chemical  activity.  They 
are  easily  oxidized,  slowly  by  contact  with  the  air  and 
quickly  by  oxidizing  agents  such  as  chromic  acid.  They 
possess  therefore  marked  reducing  properties,  and  abstract 
oxygen  from  the  oxides  of  the  noble  metals.  They  reduce 
an  ammoniacal  solution  of  silver  oxide  or  silver  salts,  caus- 


58     Organic  Chemistry  for  Students  of  Medicine 

ing  the  deposition  of  metallic  silver.  Some  of  the  aldehydes 
will  likewise  reduce  alkaline  copper  solutions,  especially 
in  the  presence  of  sodium  hydroxide.  This  property  is 
sufficiently  characteristic  and  delicate  to  be  of  use  as  a 
reagent  for  detecting  and  estimating  aldehydes  (Fehling's 
solution). 

(2)  The   aldehydes    are    easily   reduced    by   nascent 
hydrogen  to  the  same  primary  alcohols  from  which  they 
are  derived  by  oxidation  : 

CH3—  CHO  +  2  H  =  CH3CH2OH 

(3)  Conversion   into   dichlor   derivatives   of   the  type 
R—  CHZ2  (X  =  Halogen)  (31). 

(4)  Addition    reactions  :      (a)  Aldehydes    react    with 
ammonia  and  hydrocyanic  acid  to  form  addition  products. 
With  ammonia  there  is  formed  :  QJJ 

/ 

CH3—  CHO  +  HNH2  =  CH3—  CH 

\ 
NH2 

Aldehyde  ammonia 

The  addition  reaction  of  aldehyde  and  HCN  is  of 
especial  importance  because  it  forms  a  method  of  building 
up  synthetically  compounds  which  are  at  the  same  time 
alcohols  and  acids  :  QJJ 


+  HCN  =  CH3—  CH 

\ 

CN 

Ethylidene  cyanhydrin 

Ethylidene    cyanhydrin    is    readily    transformed    into 
lactic  acid  (66). 


The  Aldehydes  and  Ketones 


59 


(6)  Upon  heating  with   alcohols,    stable    ethers  —  the 
"  acetals  "  —  are  formed  : 


CH3—CH 


11 


0  + 


II 


O— CH2 
O— CH2 


-CH3 

-CH3 
=  CH3— CH(OC2H5)2  +  H20 


Acetal 


This  reaction  would  lead  to  the  supposition  that  the 
aldehydes  could  react  with  water  to  form  dialcohols  hav- 
ing both  of  the  OH  groups  linked  to  one  carbon  atom : 

OH 


CH3— CH 


OH 


CH3— CH     +  H2O 
\ 
OH 

Ethylidene  glycol 
(Hypothetical) 


This  same  compound,  the  hypothetical  ethylidene  glycol, 
we  should  expect  to  be  formed  when  ethylidene  chloride 

is  heated  with  water  : 

OH 


CH3— CH 


C12- 

H 
h 
H 

OH 
OH 

=  CH3—  CH 
\ 
OH 

+  2HC1 


This  does  not  appear  to  be  the  case.  If  it  is  formed  its 
existence  is  but  momentary,  the  compound  being  immedi- 
ately broken  down  into  the  aldehyde  and  water : 

\OH 

A 
CH3— CH  \     — >-  CH3— CHO  +  H2O 

\\ 
OH 


60     Organic  Chemistry  for  Students  of  Medicine 

From  such  considerations  the  conclusion  may  be  drawn 
that  two  hydroxyl  groups  cannot  as  a  rule  exist  bound  to 
the  same  carbon  atom.  A  molecule  of  water  is  separated 
and  an  oxygen  atom  becomes  bound  to  the  carbon  atom 
by  both  its  affinities  instead.  When  several  negative 
atoms  in  the  radical  are  introduced  in  place  of  hydrogen 
such  hydrates  can  exist.  Thus  trichlor  acetaldehyde, 
commonly  called  chloral,  combines  with  water  to  form 
chloral  hydrate: 

<H 
H 

Chloral  Chloral  hydrate 

This  compound  does  not  behave  like  a  diatomic  alcohol, 
however,  but  like  the  aldehyde  from  which  it  was  derived, 
owing  to  the  ease  with  which  water  is  separated. 

(5)  The  aldehydes  polymerize  readily.  By  polymeriza- 
tion is  meant  the  transformation  of  a  compound  into  an- 
other having  the  same  percentage  composition  with  respect 
to  the  elements,  but  with  a  molecular  weight  which  is  a 
multiple  of  that  represented  by  the  simplest  formula. 
In  the  case  of  formic  aldehyde  this  change  is  spontaneous 
at  the  ordinary  temperatures.  Acetaldehyde  does  not 
polymerize  so  readily,  but  the  change  is  brought  about  by 
the  presence  of  traces  of  hydrochloric,  sulphuric,  or  sul- 
phurous acid,  zinc  chloride,  etc.  The  reason  for  their 
catalytic  effect  is  unknown. 

Alkalies  induce  a  different  kind  of  polymerization  of 
aldehydes,  leading  to  the  formation  of  aldehyde  resins. 
For  acetaldehyde  this  is  reddish  brown  in  color,  insoluble 


The  Aldehydes  and  Ketones  61 

in  water,  but  soluble  in  alcohol,  and  gives  off  a  peculiar 
odor  which  is  characteristic. 

Formic  aldehyde,  on  the  other  hand,  in  the  presence 
of  alkali  shows  the  phenomenon  known  as  the  Cannizarro 
reaction,  in  which  through  the  action  of  water  one  molecule 
of  aldehyde  is  oxidized  to  acid,  and  another  is  reduced 
to  an  alcohol,  thus  : 

2  HCHO  +  H2O  =  CH3OH  +  HCOOH 

Formic  acid 

(6)  The  aldehydes  show  a  tendency  to  form  condensa- 
tion products  in  which  two  molecules  combine  with  a 
rearrangement  of  the  bonds  of  the  carbon  atoms,  a  hydro- 
gen atom  of  one  molecule  changing  its  linkage  from  carbon 
to  oxygen  with  the  formation  of  a  hydroxyl  group.  Thus 
when  aldehyde  stands  in  contact  with  acids  or  alkalies  it 
undergoes  what  is  known  as  the  aldol  condensation. 
There  is  formed  /3-oxybutyric  aldehyde : 

CHsCHOH-  CH2H— CHO  =  CH3— CH(OH)— CH2— CHO 

0-oxybutyric  aldehyde  (Aldol) 

This  property  of  the  aldehydes  is  of  fundamental  im- 
portance in  biology,  for  the  formation  of  carbohydrates, 
fats,  proteins,  etc.,  which  occur  in  the  animal  and  vege- 
table kingdoms. 

Formic  aldehyde  does  not  condense  through  the  influ- 
ence of  acids,  but  does  so  readily  through  the  influence 
of  very  weak  alkalies,  even  calcium  carbonate  greatly 
accelerating  the  action.  The  condensation  products  of 
formaldehyde  will  be  considered  in  detail  in  connection 
with  the  synthesis  of  the  sugars  (151). 


62     Organic  Chemistry  for  Students  of  Medicine 

(7)  With  hydroxylamine,  NH2OH,  aldehydes  condense 
to  form  aldoximes,  water  being  formed  in  the  reaction  : 

CH3GHO  +  NH2OH  =  CH3—  CH=N—  OH  +  H2O 

(8)  With   hydrazine,   NH2  —  NH2,   or   its   substitution 
products,   aldehydes  condense  to  form  hydrazones,  com- 
pounds containing  two  nitrogen  atoms  : 

CH3CHO  +  NH2—  NHR  =  CH3—  CH=N—  NHR  +  H2O 

(9)  The    aldehydes   react  with  sodium   bisulphite  to 
form  crystalline  compounds  which  are  readily  soluble  in 
water,  but  sparingly  so  in  alcohol.     These  are  looked  upon 
as  sulphonic  acid  esters  of  the  hypothetical  ethylidene 
glycol  : 

OH 

CH3—  CHO  +  HOH  =  CH3—  CH 

\ 
OH 

[OH~   H|      O 


CH3—  CH     +        S    =  CH3—  CH(OH)—  (SO3Na)+H2O 

\.  x//'^^  Aldehyde  sodium  bisulphite 

OH  NaO       O 

Such  compounds  are  easily  broken  up  on  warming  with 
a  solution  of  sodium  carbonate,  with  the  re-formation  of 
aldehydes.  These  compounds  are  of  great  importance, 
therefore,  in  the  isolation  of  aldehydes. 

Nomenclature.  —  The  aldehydes  are  named  from  the 
hydrocarbons  from  which  they  are  derived  with  the  ter- 
mination -al.  Several  of  the  more  important  ones  have 


The  Aldehydes  and  Ketones  63 

long  had  names  which  do  not  correspond  to  this  sys- 
tem of  nomenclature. 

^° 
33.   Formaldehyde.—   H—  C<      (Methanal).    Results 

XH 

from  the  regulated  oxidation  of  methyl  alcohol,  employing 
a  glowing  platinum  or  copper  spiral  as  a  catalyzer  (30). 
Other  oxidizing  agents  acting  on  methyl  alcohol  do  not 
yield  the  aldehyde.  Instead  the  oxidation  goes  farther, 
formic  acid  being  produced  (50).  It  is  a  gas  which  when 
cooled  strongly  condenses  to  a  liquid  which  boils  at  —  21°. 
Formaldehyde  is  formed  by  the  direct  union  of  hydrogen 
and  carbon  monoxide  under  the  influence  of  the  silent 
electrical  discharge.  At  600°  C.  it  is  again  dissociated 
into  hydrogen  and  carbon  monoxide  : 


H 

This  is  an  example  of  the  change  of  carbon  from  the 
divalent  into  the  tetravalent  state  and  vice  versa.  This 
type  of  change  in  the  nature  of  carbon  will  be  further  treated 
under  the  isonitriles  (40)  .  Formaldehyde  is  supplied  com- 
mercially as  a  40  %  solution  known  as  formalin. 

Formaldehyde  is  a  powerful  poison  by  reason  of  its 
power  to  react  with  the  proteins  of  the  tissues,  destroy- 
ing their  special  properties  as  components  of  the  living 
protoplasm.  It  is  employed  in  disinfection  and  in  the 
preservation  and  hardening  of  anatomic  specimens. 

With  ammonia  it  forms  hexamethylenetetramine,  or 
urotropin,  a  feebly  basic  crystalline  solid,  soluble  in  1.8 


64     Organic  Chemistry  for  Students  of  Medicine 

parts  of  water  and  10  parts  of  alcohol.     (Sometimes  also 
called  aminoform  and  cystamin.) 

6  CH2O  +  4  NH3  =  (CH2)6N4  +  6  H2O 

It  is  employed  internally  in  medicine  as  an  antiseptic. 
It  is  absorbed  without  decomposition  and  passes  through 
the  kidneys  in  great  measure  unchanged,  but  the  urine 
after  its  administration  frequently  contains  traces  of 
formaldehyde. 

Polymerization  of  formaldehyde.  —  According  to  the 
conditions  formaldehyde  polymerizes  in  different  ways. 

Paraformaldehyde  is  formed  when  formalin  is  evapo- 
rated on  a  water  bath.  It  is  a  white  solid  which  melts 
at  about  153°  and  on  strongly  heating  evolves  formalde- 
hyde. It  is  looked  upon  as  (CH20)2. 

Trioxymethylene  (CH2O)3  is  a  white  crystalline  com- 
pound which  separates  from  solutions  of  formaldehyde  on 
standing.  This  substance  differs  from  paraldehyde  in 
that  it  does  not  dissolve  in  water,  alcohol,  or  ether.  It 
is  formed  spontaneously  when  formaldehyde  solution  is 
allowed  to  evaporate  at  ordinary  temperatures.  It  passes 
into  formaldehyde  again  on  heating. 

Formose  (CH2O)e  is  a  condensation  product  resulting 
from  the  action  of  milk  of  lime  on  formaldehyde.  It  con- 
sists of  a  mixture  of  sugars  of  the  glucose  group  (151). 

Methylal,  CH2(OCH3)2,  may  be  looked  upon  as  derived 
from  one  molecule  of  formaldehyde  and  two  of  methyl 
alcohol : 


HCH 


b  +  {J 


=  CH2(OCH3)2.  +  H20 


The  Aldehydes  and  Ketones  65 

It  is  therefore  an  ether  of  the  hypothetical  glycol 

OH 
CH2< 
XOH 

It  is  employed  as  a  soporific  and  anesthetic,  B.  P.  42°. 
It  is  soluble  in  water,  in  alcohol,  and  in  oils. 

Acetaldehyde  (acetic  aldehyde,  ethanal,  aldehyde), 
CH3CHO.  The  preparation  of  this  aldehyde  by  the 
oxidation  of  alcohol  has  already  been  described  (30).  It 
is  purified  by  conversion  into  aldehyde  ammonia,  which  is 
filtered  and  washed  with  ether.  The  aldehyde  ammonia 
is  afterward  distilled  with  dilute  sulphuric  acid. 

It  is  obtained  in  large  quantities  as  a  by-product  in  the 
distillation  of  fermented  solutions  in  the  manufacture  of 
spirits.  It  is  a  colorless  liquid,  B.  P.  21°,  specific  gravity 
about  .8.  It  has  a  characteristic  suffocating  odor.  It  is  a 
solvent  for  sulphur,  phosphorus  and  iodine.  Aldehyde 
dissolves  readily  in  water,  alcohol,  and  ether.  PCU  con- 
verts it  into  ethylidene  chloride  (31). 

Paraldehyde  (C2H4O)s  is  formed  when  a  little  HC1, 
COCk,  S02,  or  ZnCl2  is  added  to  aldehyde.  It  is  formed 
with  a  violent  reaction  on  adding  concentrated  sulphuric 
acid  to  aldehyde. 

It  is  a  colorless  liquid  which  crystallizes  below  10.5°, 
B.  P.  124°.  It  possesses  a  peculiar,  aromatic,  suffocating 
odor  and  a  warm  taste ;  is  soluble  in  alcohol,  ether,  oils 
and  chloroform,  and  in  ten  parts  of  water.  Specific 
gravity,  .995  at  15°. 

Paraldehyde  is  a  hypnotic  and  antispasmodic,  and  is  used 
in  medicine  to  a  considerable  extent. 


66     Organic  Chemistry  for  Students  of  Medicine 

Paraldehyde  has  the  constitution  : 

,CH3 

O—  CH<  ' 
CH3—  CH<( 


It  reacts  in  the  same  way  as  aldehyde  with  PC15,  but 
does  not  react  with  hydroxylamine,  ammonia,  or  sodium 
bisulphite.  The  ease  with  which  paraldehyde  is  recon- 
verted into  aldehyde  by  distillation  with  dilute  sulphuric 
acid  is  taken  as  evidence  that  the  carbon  atoms  are  linked 
through  oxygen  and  not  carbon  directly  to  carbon.  The 
bond  between  two  carbon  atoms  is  much  too  stable  to  be 
broken  in  this  manner. 

Metaldehyde  (C2H4O)3  is  formed  by  the  action  of  gaseous 
HC1  or  SO2  in  aldehyde  cooled  to  the  temperature  of  a 
freezing  mixture.  It  is  a  white  crystalline  substance, 
insoluble  in  water,  soluble  in  chloroform,  benzine,  slightly 
soluble  in  alcohol  and  in  ether.  It  sublimes  at  112-115° 
with  partial  conversion  into  aldehyde.  It  is  employed 
as  a  hypnotic  and  sedative. 

/OH 

Aldehyde  ammonia,  CHs  —  CH<^        ,  is  prepared  by 

XNH2 

passing  dry  ammonia  gas  into  a  solution  of  aldehyde  in 
ether.  It  forms  white  crystals  which  are  readily  soluble 
in  water,  but  slightly  soluble  in  ether;  M.  P.  70-80°. 
It  distills  undecomposed  at  100°. 

34.  Chloral,  Trichloracetaldehyde,  CC13—  CHO,  a 
liquid  with  a  sharp  and  characteristic,  disagreeable  odor, 
B.  P.  98°,  is  formed  as  the  end  product  of  the  action  of 


The  Aldehydes  and  Ketones  67 

chlorine  on  alcohol.  When  impure  it  easily  changes  to  a 
crystalline  solid  polymerization  product,  metachloral, 
but  is  converted  back  into  chloral  on  heating  It  is 
readily  oxidizable  to  trichloracetic  acid.  With  alkalies 
it  is  decomposed  into  chloroform  and  a  salt  of  formic  acid  : 
CC13—  CHO  +  KOH  =  CHC13  +  HCOOK 

Potassium 
formate 

Chloral  readily  adds  a  molecule  of  water,  forming  chloral 


hydrate,  CC13  —  CH<^       •     This  is  a  crystalline  substance 

XOH 

soluble  in  water,  which  melts  at  57°,  and  boils  at  97°  with 
dissociation  into  chloral  and  water.  It  is  employed  as  a 
soporific  and  antiseptic.  Strong  sulphuric  acid  with- 
draws a  molecule  of  water  from  it,  forming  jchloral. 

CH2OH 
35.   Glycol  Aldehyde,  |  ,  may  be  regarded  as  oxy- 

CHO 

acetaldehyde  or  as  the  half  aldehyde  of  glycol.  It  shows 
the  properties  of  both  an  alcohol  (12)  and  an  aldehyde. 
It  is  formed  by  the  oxidation  of  glycol  or  by  the  reaction 
of  brom  acetaldehyde  with  barium  hydroxide  : 

CH2OH  CH2OH 

|  +0=|  +H20; 

CH2OH  CHO 

CH2Br  CH2OH 

|  +  HOH  =  |  +HBr 

CHO  CHO 

It  is  a  sweet,  crystalline  compound  and  is  the  simplest 
substance  having  the  properties  of  the  sugars  (see 
carbohydrates,  150). 


68     Organic  Chemistry  for  Students  of  Medicine 

CHO 
Glyoxal,  |       ,  results  from  the  oxidation  of  glycol  or 

CHO 

may  be  prepared  by  oxidizing  acetaldehyde  with  nitric 
acid  at  ordinary  temperatures.     It  is  not  crystallizable,  but 
is  a  solid  when  free  from  water.     It  forms  a  bisulphite 
compound  which  is  useful  in  its  isolation. 
CH2OH 

I 

36.  Glyceraldehyde,  CHOH,  results  from  the  oxidation 

CHO 

of  glycerol  by  sodium  hypobromite  or  by  hydrogen  per- 
oxide in  the  presence  of  ferrous  sulphate.  There  is 

CH2OH 

always  formed  with  it  the  isomeric  compound,  CO 

CH2OH 

Dihydroxyacetone 

the  latter  representing  the  principal  product  of  the  oxida- 
tion. Glyceraldehyde  can  also  be  prepared  from  acrylic 
aldehyde  (85),  which  confirms  its  structure. 

37.  Ketones.  —  When  secondary  alcohols  are  oxidized 
they  lose  two  hydrogen  atoms  and  yield  ketones,  com- 
pounds containing  the  carbonyl  group  in  a  secondary 
position : 


(1)  CHg— CHOH— CHg  +O  =  CH3— CO— CH3  +  H2O 

Secondary  propyl  Dimethylketone 

alcohol  (Acetone) 


They  contain  the  carbonyl  group  linked  to  two  carbon 
atoms,  and  may  be  looked  upon  as  aldehydes  in  which  the 


The  Aldehydes  and  Ketones  69 

H  of  the  CHO  group  has  been  replaced  by  an  alkyl  group, 
or  as  organic  acids  whose  hydroxyl  is  exchanged  for  alkyl. 
The  existence  of  ketones  having  less  than  three  carbon 
atoms  is  theoretically  not  possible. 


rn    r  ru 

\)  \) 

Aldehyde  Ketone 

(2)  Acetone,  CH3—  CO—  CH3,  is  also  formed  by  the 
dry  distillation  of  the  calcium  or  barium  salt  of  acetic  acid  : 


CaCO3 


(3)  By  employing  acids  having  longer  carbon  chains 
ketones  with  higher  alkyl  groups  are  formed.  Thus  a 
mixture  of  equal  molecules  of  calcium  acetate  and  cal- 
cium propionate,  CH3 — CH2 — COOca  (ca  =  i  Ca),  yields  a 
mixed  ketone : 


Oca 

CaC°3 


C3H5 

R 

I 
(4)  Alkyl  dichlorides  of  the  type      CC12  react  with 

R 

water  to  form  ketones  : 


70    Organic  Chemistry  for  Students  of  Medicine 

CH3  CH3 

I  I 

CC12  +H2O  =CO  +  2HC1 

I  I 

CH3 


(5)  Zinc  alkyl  reacts  with  the  acid  chlorides,  forming 
ketones  : 

CH3—  COC1  +  CH3zn  =  CH3—  CO—  CH3  +  i  ZnCl2 

Acetyl  chloride  (zn   =  i  Zn) 

Nomenclature.  —  The  name  of  the  alkyl  radical  followed 
by  the  ending  ketone  indicates  the  structure  of  these  com- 
pounds, as  dimethyl,  diethyl,  methyl-ethyl  ketone,  etc. 
This  also  indicates  the  isomerism  among  the  ketones,  which 
may  be  due  to  :  (a)  The  alkyl  groups  having  the  normal  or 
branched  structure,  or  (6)  to  the  position  of  the  CO  group 
in  similar  carbon  chains.  Thus  a  ketone  containing  six 
carbon  atoms  may  be  methyl-butyl  ketone,  or  ethyl- 
propyl  ketone,  CH3—  CO—  C4H9,  or  C2H5—  CO—  C3H7. 

Chemical  Behavior.  —  (1)  The  ketones,  like  the  alde- 
hydes, are  reducible  to  the  alcohols  from  which  they  are 
formed  on  oxidation,  thus  : 

CH3  CH3 

I  I 

CO  +  2H  =  CHOH 

I  I 

CH3  CH3 

Acetone  Isopropyl  alcohol 

Ketones  yield  on  reduction  therefore  secondary  alcohols. 

(2)  Ketones  differ  markedly  from  aldehydes  in  their  be- 

havior toward  oxidizing  agents.     They  yield  acids  having 


The  Aldehydes  and  Ketones  71 

a  lesser  number  of  carbon  atoms  than  the  ketones  them- 
selves, whereas  the  aldehydes  yield  acids  of  the  same  num- 
ber of  carbon  atoms,  thus  : 


CO  +  3  O  =  CH3—  COOH  +  HCOOH 

Acetic  acid  Formic  acid 

CH3 

Acetone 

Methyl-ethyl  ketone  may  be  oxidized  in  two  ways,  thus 
CHs—  CO—  CH2—  CH3,  yielding  2  CH3COOH 


CH3— CO— CH2— CH3,  yielding 

CH3— CH2— COOH  +  HCOOH 

Propionic  acid  Formic  acid 

Under  the  influence  of  oxidizing  agents,  as  chromic  acid, 
as  well  as  in  the  animal  body,  the  cleavage  of  the  carbon 
chain  in  such  compounds  never  follows  one  line  to  the 
exclusion  of  all  others.  There  results  a  certain  amount  of 
each  of  the  possible  oxidation  products.  In  the  case  of 
methyl-ethyl  ketone,  formic,  acetic,  and  propionic  acids 
would  be  formed,  but  not  necessarily  in  equivalent  amounts. 

(3)  The  ketones  are  converted  by  PCU  into  dichlorides 
of  the  type  R2=CCl2.  It  has  been  pointed  out  above 
that  these  can  react  with  water  with  the  re-formation  of 
ketones. 

The  carbonyl  group  of  the  ketones  shows  less  tendency 
to  unite  with  water  and  with  alcohol  than  in  the  case  of 


72     Organic  Chemistry  for  Students  of  Medicine 

the  aldehydes.  With  hydrocyanic  acid,  however,  there 
are  formed  addition  products  called  nitriles.  These 
compounds  are  of  the  greatest  importance  in  synthetic 
chemistry;  They  will  be  dealt  with  in  detail  later  (40, 
156). 

(4)  The  ketones  differ  from  the  aldehydes  in  that  they 
do  not  polymerize.     They  do  form  condensation  products, 
however,  analogous  to  the  behavior  of  aldehydes.     Ace- 
tone, when  acted  upon  by  HC1,  H2SO4,  KOH,  CaO,  and 
other  reagents,  condenses  with  the  separation  of  water. 
Two  molecules  unite  to  form    mesityl  oxide,    CeHioO; 
three  molecules  condense  to  form  mesitylene  (172). 

(5)  Like   the   aldehydes,   the   ketones   condense   with 
hydroxylamine  to  form  ketoximes  (31). 

CH3Vx)  +  H2N—  OH  =  CH3N>C=N—  OH  +  H20 
CH3/  CH3/ 

Acetone  Acetoxime 

Acetoxime  on  heating  with  concentrated  HC1  decom- 
poses into  acetone  and  hydroxylamine. 

In  a  similar  manner,  ketones  react  with  the  amino 
group  of  the  hydrazines,  forming  hydrazones  : 

\CO  +H2N—  NHR  =  (CH3)2=C=N—  NHR  +H2O. 


Those  ketones  which  contain  the  radical  CH3  —  CO  —  , 
and  a  few  others,  form  addition  products  with  sodium 
bisulphite  in  a  manner  similar  to  the  aldehydes  : 

(CH,),=CO  +HNaS03  = 


The  Aldehydes  and  Ketones      73 

These  when  heated  with  sodium  carbonate  solution 
regenerate  ketones.  These  compounds  are  of  great 
value  in  separating  ketones  from  mixtures  and  in  purify- 
ing them. 

38.  Acetone,  CH3 — CO — CH3,  is  the  simplest  and 
most  common  ketone.  It  is  a  liquid  with  a  characteristic 
ethereal  odor,  B.  P.  56°. 

Its  specific  gravity  at  0°  is  0.81.  It  is  soluble  in  water, 
but  much  less  so  in  solutions  of  inorganic  salts.  This 
property  is  made  use  of  in  separating  it  from  water  solu- 
tions. It  likewise  dissolves  in  all  proportions  in  alcohol 
and  in  ether. 

It  is  a  very  stable  substance  toward  oxidizing  agents, 
not  being  attacked  by  cold  KMn04  solutions,  but  it  is 
oxidized  to  acetic  and  formic  acids  by  chromic  acid.  It  is 
very  inflammable  and  should  be  handled  with  caution 
against  the  ignition  of  its  vapors.  Acetone  occurs  in 
normal  urine  in  very  small  amounts,  but  is  present  in 
large  quantities  in  the  urine  of  diabetic  patients.  Its 
formation  in  the  body  will  be  explained  later  (see  aceto- 
acetic  acid,  127). 

Lieben's  iodoform  test  for  acetone  depends  upon  the 
fact  that  alkaline  iodine  solutions  oxidize  acetone  and 
form  triiodo  methane  or  iodoform.  A  solution  of  iodine 
and  KI  is  added  to  the  solution  to  be  tested  and  then 
dilute  sodium  hydroxide  added  drop  by  drop.  The  iodine 
color  is  discharged  at  once  and  there  separates  at  once  a 
crystalline  deposit  of  iodoform.  The  reactions  involved 
are: 


74     Organic  Chemistry  for  Students  of  Medicine 
CH3— CO— CH3  +  3  KIO  =CH3— CO— CI3  +3  KOH 

Potassium  Triodoacetone 

hypo-iodite 

CH3— CO— CI3  +  KOH  =  CH3— COOK  +  CHI3 

Potassium  acetate        lodoform 

u 

The  iodoform  can  be  extracted  with  ether,  and  on  eva- 
poration of  the  latter  is  left  as  yellow  hexagonal  plates 
having  a  characteristic  odor.  On  the  formation  of  iodo- 
form under  these  conditions  depends  the  qualitative  detec- 
tion of  acetone  devised  by  Vournasos.  This  test  is  not 
characteristic  for  acetone  but  is  given  by  alcohol  and  alde- 
hyde as  well. 

Acetone  in  the  presence  of  alkali  dissolves  mercuric  oxide, 
and  this  property  is  made  use  of  in  testing  for  its  presence 
in  solution.  A  mercuric  salt,  as  the  chloride  or  nitrate,  is 
added  to  the  solution  to  be  tested,  and  then  sodium  hy- 
droxide to  strong  alkalinity,  and  then  an  equal  volume 
of  alcohol.  The  solution  is  then  filtered  and  the  filtrate 
acidified  with  HC1  and  a  layer  of  (NH^S  solution  poured 
carefully  upon  it.  If  mercury  is  precipitated  as  the  black 
sulphide,  it  indicates  a  positive  test.  Aldehydes  also  give 
this  reaction. 

Acetone  forms  with  mercuric  oxide  the  compound 
2  CH3— CO— CH3  •  3  HgO,  insoluble  in  dilute  acetic  acid ; 
also  a  white  crystalline  compound, 

CH3— CO— CH3  -  (HgSO4)2  •  3  HgO 

The  latter  compound  is  very  insoluble  in  dilute  acetic 
acid,  and  its  formation  is  the  basis  of  the  test  for  acetone 
designed  by  Deniges. 

Acetone    does    not   reduce    Fehling's    solution.     With 


The  Aldehydes  and  Ketones  75 

o-nitro  benzaldehyde  and  sodium  hydroxide  acetone  reacts 
to  form  indigo  (326). 

Sulphonal,  a  substance  used  as  a  soporific,  is  derived 
from  the  condensation  product  of  acetone  and  mercaptan. 
When  these  are  mixed  and  treated  with  hydrochloric  acid 
they  condense  with  the  separation  of  water : 

(CH3)2=CO  +  2  HS— C2H6  =  (CH3)2=C(SC2H5)2  +  H2O 

Acetone  Mercaptan 

On  oxidation  this  product  yields  a  disulphone,  which  is 
sulphonal. 

(CH3)2=C(SC2H5)2  +  40  =  (CH3)2=C(S02C2H5)2 

Sulphonal 

Several  derivatives  of  higher  ketones  have  also  been  intro- 
duced. Trional  is  made  from  ethyl-methyl  ketone,  and 
tetronal  contains  four  ethyl  groups. 

39.  Dihydroxyacetone,  CH2OH— CO— CH2OH,  results 
from  the  oxidation  of  glycerol  with  sodium  hypobromite 
or  nitric  acid.  Its  formation  is  accompanied  with  that 
of  its  isomer  glyceraldehyde  (36).  The  structure  of 
dihydroxyacetone  is  established  by  the  fact  that  it  forms, 
with  hydrocyanic  acid,  an  oxynitrile  (32)  which  by 
chlorination  and  subsequent  reduction  is  converted  into 
isobutyric  acid : 

CH2OH  CH2OH 

I  I /OH 

CO        +HCN=C(         +2H2O 

|          >      |\CN * 

CH2OH  CH2OH 


76     Organic  Chemistry  for  Students  of  Medicine 

CH2OH  CH2C1 

I /OH  |/C1 

POC13C< 
>  i  X 


<XX)H  ~  XCOOH 

CH2OH  CH2C1 

J   +  6H 
CH3 

CH— COOH 
CH3 

Isobutyric  acid 

Dihydroxyacetone  is  chemically  related  to  the  sugars 

(150). 


CHAPTER  V 

THE  NITRILES  AND  THEIR   REDUCTION    PRODUCTS, 
THE   AMINES 

40.  The  Nitriles  and  Isonitriles.  —  It  has  been  pointed 
out  (28)  that  alkyl  halides  react  with  certain  salts  of 
acids,  yielding  esters,  and  that  these  on  hydrolysis  are 
resolved  into  alcohols  and  acids.  The  behavior  of  the 
salts  of  hydrocyanic  acid  is  different  from  others  in  that  it 
yields  two  classes  of  derivatives  which  do  not  go  back  into 
alcohol  and  hydrocyanic  acid,  but  yield  a  new  type  of 
compound  on  hydrolysis  : 

CH3I  +  KCN  =  CH3—  CN  +  KI 

Potassium  Methyl 

cyanide  cyanide 

Methyl  cyanide  is  a  colorless  liquid  boiling  at  81°. 
Its  specific  gravity  is  .805  at  0°.  It  is  soluble  in  water  and 
is  combustible. 

On  being  warmed  with  either  acids  or  alkalies  nitriles 
add  water  (saponification)  and  are  converted  into  acid 
and  ammonia  : 


CH3—  CN  +  2  H2O  =  CH3—  COOH  +  NHs 

Acetic  acid 

This  behavior  is  analogous  to  that  of  hydrocyanic  acid, 
which  when  heated  with  dilute  acids  is  converted  into 
formic  acid  and  NH3  : 

HCN  +  2  H2O  =  HCOOH  +  NH3 

Formic  acid 

77 


78     Organic  Chemistry  for  Students  of  Medicine 

Aside  from  the  importance  of  the  nitriles  for  the  forma- 
tion of  acids  they  are  of  the  greatest  importance  for  build- 
ing up  carbon  chains.  Thus  any  alcohol  can  be  converted 
by  PCI 5  into  its  alkyl  halide  derivative,  and  this  on  being 
converted  into  a  nitrile  gains  a  new  carbon  atom : 

^>  CH3C1 >•  CH3— CN 

-->  CH3— COOH 

Two  practices  prevail  regarding  the  nomenclature  of  the 
alkyl  cyanides.  They  are  called  methyl  cyanide,  ethyl 
cyanide,  propyl  cyanide,  etc.,  but  are  more  frequently 
called  nitriles,  and  are  then  named  after  the  acid  which 
they  yield  on  hydrolysis.  CH3 — CN  is  called  aceto- 
nitrile;  CH3 — CH2 — CN,  propionitrile,  etc. 

Nascent  hydrogen  reduces  the  nitriles  to  compounds 
called  amines.  The  process  is  one  of  addition  of  hydrogen : 

CH3CN  +  4  H  =  CH3— CH2— NH2 

Ethyl  amine 

The  amines  may  be  looked  upon  as  ammonia  in  which 
one  hydrogen  atom  is  replaced  by  an  alkyl  group  (see 
amines,  43). 

The  formation  of  carboxyl  and  ammonia  on  hydrolysis 
and  of  amines  on  reduction  shows  that  in  the  nitrile  the 
nitrogen  cannot  be  directly  linked  to  the  alkyl  radical. 
The  CN  group  is  linked  to  the  alkyl  group  by  its  carbon. 

Isonitriles.  —  If  instead  of  KCN  we  cause  alkyl  halide 
to  react  with  silver  cyanide,  there  is  obtained  a  colorless 
liquid  slightly  soluble  in  water  which  has  an  intolerable 


The  Nitriles  and  Amines  79 

odor  and  poisonous  properties.  It  has  the  same  percent- 
age composition  with  respect  to  the  elements  as  ethyl 
nitrile,  and  is  isomeric  with  it : 

CH3— CH2I  +  AgNC  =  CH3— CH2— NC 

Ethyl  isocyanide 

This  substance  behaves  on  heating  with  water  or  with 
acids  in  a  manner  entirely  different  from  ethyl  cyanide  : 

CH3— CH2— N  =  C  +  2  H2O  = 

CH3— CH2— NH2  +  HCOOH 

Ethyl  amine  Formic  acid 

In  this  compound  the  carbon  atom  of  the  isocyanide  is 
split  off,  which  indicates  that  the  nitrogen  is  linked  directly 
to  the  ethyl  group.  Unlike  the  nitriles  they  are  very 
stable  toward  alkalies. 

From  the  above  considerations  it  appears  that  the  silver 
salt  of  hydrocyanic  acid  has  a  structure  different  from  that 
of  potassium  cyanide. 

A  great  interest  attaches  to  the  isonitriles  or  alkyl 
isocyanides  because  they  apparently  form  an  exception 
to  the  general  rule  that  carbon  in  organic  compounds  is 
always  tetravalent.  Several  possible  assumptions  may 
be  made  regarding  the  structure  of  these  compounds. 
The  carbon  atom  may  be  in  a  divalent  state  (I) ;  or  two 
of  its  valences  may  be  free,  or  polarized  (II) ;  or  the 
nitrogen  may  exist  in  the  pentavalent  state  (III)  as  it  is 
known  to  be,  e.g.,  in  ammonium  hydroxide,  all  four 
valences  of  the  carbon  atom  being  in  union  with  nitrogen. 

R— N  =  C        R— N  =  C<(  or  R— N  =  C=2        R— N  =  C 
i  ii  in 


80     Organic  Chemistry  for  Students  of  Medicine 

The  extensive  studies  of  Neff  have  afforded  the  most 
satisfactory  explanation  of  the  structure  of  the  isonitriles, 
and  the  principles  which  they  disclosed  are  of  great  im- 
portance in  elucidating  the  nature  of  reactions  generally 
among  organic  compounds.  A  discussion  of  some  reac- 
tions which  throw  light  on  the  behavior  of  these  compounds 
will  be  of  value. 

The  isonitriles  are  assumed  by  Neff  to  possess  the  struc- 
ture represented  by  R  —  N  =  C,  but  there  exists  a  small 
number  of  the  molecules  dissociated  into  the  "  active  " 

form  R  —  N  =  C\,  these  being  in  dynamic  equilibrium 
with  the  form  R  —  N  =  C  which,  either  because  its  car- 
bon is  divalent,  or  because  two  of  its  bonds  of  affinity 
are  polarized  or  latent,  is  incapable  of  any  chemical 
activity  whatever.  The  percentage  of  "  active  "  mole- 
cules varies  with  the  nature  and  mass  of  R,  a  fact  shown 
by  the  variation  in  the  chemical  activity  of  compounds  of 
this  type. 

1.  Halogens  (chlorine,  bromine,  iodine),  speed  of  reac- 
tion in  the  order  named,  are  absorbed  by  the  alkyl  iso- 
cyanides  with  great  evolution  of  heat,  forming  dihalogen 
derivatives  : 

X 
—  N  =  C 


/X 

->  R—  N  =  C<          (X  =  Halogen) 

NT 

2.  Oxygen  and  sulphur  convert  the  isocyanides  into 
isocyanates  and  isothiocyanates  respectively  : 


The  Nitriles  and  Amines  81 

R—  N  =  C 
R—  N  =  C<    +S  ->R— 


3.  Alcohols  in  the  presence  of  alkali  are  absorbed,  giving 
compounds  known  as  imido  ethers  : 

H  /H 

|         ->•  R—  N  =  CC 
O—  R  \O—  R 


R—  N  =  C     +  ->•  R—  N  =  CC 

\ 


4.  Hydrogen  sulphide  and  mercaptans  give  the  addition 
products  :  * 

/       H\  /H 

R—  N  =  C<  H-       >S  ->  R—  NH—  C<^ 

H/  ^S 

/  /H 

R—  N  =  C<  +  HS—  R  -^  R—  N  =  C< 

\SR 

A  striking  property  of  these  addition  products  of  the 
isonitriles  is  their  low  point  of  dissociation,  i.e.  the  car- 
bon atom  which  has  absorbed  the  X  —  Y,  thus  becoming 
tetravalent,  is  unable  to  hold  X  —  F  above  certain  tem- 
perature limits.  There  is  therefore  a  certain  temperature, 
varying  with  the  nature  of  all  the  groups  in  the  compound, 
at  which  the  carbon  atom  becomes  spontaneously  divalent, 
the  X  —  Y  becoming  dissociated,  thus: 

/X  / 

R_N  =C       ±£  R—  N  =C(  +  X—  Y. 


The  dissociation  is  very  slight  at  low  and  moderate  tem 
peratures  and   increases  as  the  temperature   is   raised. 


82     Organic  Chemistry  for  Students  of  Medicine 

There  is  an  equilibrium  between  divalent  and  tetravalent 
carbon. 

Dynamic  equilibrium  implies  a  set  of  conditions  in 
which  if  one  of  the  components  of  a  system  is  withdrawn, 
it  is  replaced  by  the  further  dissociation  of  a  part  of  the 
undissociated  component,  so  that  a  definite  relationship 
always  exists  among  the  components  of  the  system.  Thus 
the  dihalogen  addition  products  of  the  alkyl  isocyanides 
are  converted  back  into  the  alkyl  isocyanides  if  kept  in 
contact  with  zinc  dust,  the  latter  serving  simply  to  tie 
up  progressively  and  remove  from  the  system  the  small 
amount  of  halogen  which  is  dissociated.  The  dissociation 
becomes  progressive  under  these  conditions  and  the  reac- 
tion goes  to  completion  : 

/Cl 

R—  N  =C         +  Zn  ->  R—  N  =  C  +  ZnCl2 


The  isonitriles  have  a  marked  tendency  to  polymerize 
and  form  resinous  products.  This  is  without  doubt  due 
to  the  combination  of  the  active  dissociation  products 
with  each  other,  the  reaction  in  this  case  being  non- 
reversible. 

41.  Fulminic  Acid.  —  When  KCN  is  oxidized  there  is 
produced  potassium  cyanate,  KCNO.  There  appears  to 
exist  an  acid  isomeric  with  cyanic  acid  in  fulminic  acid. 
The  free  acid  is  not  known  in  a  state  of  purity,  but  its 
salts,  especially  the  mercuric  and  the  silver  fulminates,  are 
well  known.  The  formulae  for  these  compounds  corre- 
spond to  Hg(ONC)2  and  AgONC. 


The  Nitriles  and  Amines  83 

On  hydrolysis  the  fulminates  yield  hydroxylamine  and 
a  salt  of  formic  acid  : 

HONC+  2H20  =  HONH2  +H— COOH 

Fulminic  Hydroxyl-  Formic  acid 

acid  amine 

The  formula  HONC  for  fulminic  acid  can  be  accepted 
only  by  assuming  the  existence  of  carbon  in  a  divalent 
form.  This  assumption  is  not  ordinarily  considered 
tenable,  but  there  is  one  compound  of  carbon,  viz. 
carbon  monoxide,  which  must  certainly  contain  diva- 
lent carbon. 

C-N 
42.    Cyanamide.  —    |       may  be  regarded   as  a    com- 

NH2 

pound  in  which  a  hydrogen  of  ammonia  is  replaced  by  the 
cyanide  radical.  The  latter  is  strongly  negative  and 
exerts  an  influence  upon  the  behavior  of  the  hydrogen 
atoms  of  the  NH2  group.  While  ammonia  is  capable  of 
forming  metallic  derivatives,  these  are  not  readily  formed. 
Sodium  and  potassium  must  be  strongly  heated  in  the 
presence  of  ammonia  before  the  amides  of  these  metals  are 
formed  (NaNH2,  KNH2)  and  magnesium  must  be  heated 
to  incandescence  in  order  to  form  the  nitride.  The  hydro- 
gen atoms  of  the  NH2  or  amide  group  in  cyanamide  are 
much  more  easily  replaced  by  metals.  Silver  cyanamide, 
AgHN — C=N,  is  a  yellow  amorphous  compound, 
formed  by  adding  soluble  silver  salts  to  solutions  of  cyan- 
amide.  Cyanamide  is  obtained  as  the  calcium  compound 
by  passing  nitrogen  over  heated  calcium  carbide : 

CaC2  +  N2  =  CN  •  N  =Ca  +  C 

Calcium  cyanamide 


84     Organic  Chemistry  for  Students  of  Medicine 

It  is  now  made  on  a  large  scale  and  is  used  as  a  fertilizer. 
Calcium  cyanamide  is  slowly  decomposed  by  water,  form- 
ing calcium  carbonate  and  ammonia  : 

N-C— N  =  Ca  +  3H2O  =  2NH3  +  CaCO3 
As  an  intermediate  product  cyanic  acid  is  formed : 
N  =  C— N  =  Ca  +  3  H20  =  CN— OH  +  NH3  +  Ca(OH)2 

Cyanic  acid 

Cyanic  acid  readily  reacts  with  water  to  form  ammonia 
and  carbon  dioxide : 

N-C— OH  +  H20  =  NHs  +  C02 

Cyanamide  is  a  crystalline  compound  readily  soluble  in 
water,  alcohol,  and  ether.  It  melts  at  40°. 

43.  The  Amines.  —  The  hydrogen  atoms  of  ammonia 
may  be  replaced  by  alkyl  groups,  forming  a  class  of  com- 
pounds called  amines,  which  have  a  great  biological  im- 
portance. Many  of  them  occur  in  nature,  especially  as 
products  of  the  action  of  putrefactive  bacteria  on  proteins. 
The  amines  containing  the  lower  alcohol  radicals  closely 
resemble  ammonia  in  odor  and  are  even  more  strongly 
basic  than  the  latter.  Like  ammonia,  they  form  white 
clouds  of  finely  divided  salts  when  brought  into  contact 
with  volatile  acids.  The  union  with  acids  is  attended 
with  the  evolution  of  heat.  They  behave  like  ammonia 
in  forming  double  salts  with  salts  of  the  heavy  metals 
such  as  platinic  or  gold  chloride. 

They  differ  from  ammonia  in  being  combustible.  The 
lower  members  are  readily  soluble  in  water.  The  solubil- 
ity in  water  diminishes  with  increasing  length  of  the  carbon 


The  Nitriles  and  Amines  85 

chains.  The  volatility  likewise  diminishes  with  increasing 
molecular  weight,  the  highest  members  being  solids  in- 
soluble in  water  and  without  odor.  These  are,  however, 
still  soluble  in  alcohol  and  ether  and  are  basic  in  character, 
readily  combining  with  acids  to  form  salts.  The  specific 
gravity  of  all  the  amines  is  considerably  less  than  that  of 
water.  ' 

Classification.  —  The  amines  are  termed  primary,  secon- 
dary, or  tertiary,  depending  on  whether  one,  two,  or  three 
hydrogen  atoms  of  ammonia  are  replaced  by  alkyl  groups, 

e-9-:        CH3— NH2         (CH3)2=NH        (CH3)3=N 

Methyl  amine  Dimethyl  amine  Trimethyl  amine 

(primary)  (secondary)  (tertiary) 

The  characteristic  group  of  the  primary  amines  is  there- 
fore — NH2,  of  the  secondary  amines  =NH,  and  of  the 
tertiary  amines  =N. 

The  relation  of  the  amines  to  the  hydrocarbons  is  shown 
by  their  synthesis  from  the  alkyl  halides  and  ammonia : 

CH3I  +  NH3  =  CH3— NH2  •  HI 

Methyl  ammonium  iodide 

Methyl  ammonium  iodide  is  a  salt  entirely  analogous 
to  ammonium  iodide.  On  the  .  treating  this  salt  with  an 
alkali,  methyl  amine  is  liberated  : 

CHa— NH2  •  HI  +  NaOH  =  CH,— NH2  +  Nal  +  H2O. 

The  amines  show  their  character  as  substituted  ammo- 
nias in  uniting  with  water  to  form  hydroxides : 

CH3— CH2— NH2  +H2O  =  C2H5NH3OH 

Ethylamine  Ethyl  ammonium  hydroxide 

(CH3)2  =NH  +  H2O  =  (CH3)2  =NH2OH 

Dimethylamine  Dimethyl  ammonium  hydroxide 


86    Organic  Chemistry  for  Students  of  Medicine 

The  secondary  amines  are  formed  from  the  primary  by 
the  further  action  of  alkl  halide  : 


CH3I  =  (CH3)2  =NH  •  HI 
(CH3)2  =  NH  -  HI  +  NaOH  =  (CH3)2  =  NH2OH  +  Nal 


(CH3)2=NH  +C2H5I  =  •  HI 


25 

Dimethyl  ethyl  ammonium  iodide 


Dimethyl-ethyl  ammonium  hydroxide 

Trimethylamine  is  formed  by  the  action  of  alkyl  halide 
upon  dimethylamine  : 

(CH3)2  =  NH  +  CH3I  =  (CH8)s  =  N-  HI 

Trimethyl  ammonium  iodide 

Trimethyl  ammonium  iodide  on  treatment  with  an 
alkali  yields  trimethylamine  in  a  manner  analogous  to  the 
primary  and  secondary  compounds.  Trimethylamine 
can  likewise  take  up  a  molecule  of  methyl  halide  (or  other 
alkyl  halide)  and  form  tetramethyl  ammonium  iodide  : 

(CH3)3=N  +CH3I  =  (CH3)4  =  NI 

Tetramethyl  ammonium  iodide 

These  compounds  are  known  as  •  quaternary  bases. 
They  are  not  capable  of  reacting  with  hydroxides  of  the 
alkali  metals.  They  are  so  stable  that  they  can  be  boiled 
with  sodium  hydroxide  without  decomposition.  The 
liquid  and  gaseous  amines  are  volatile  with  steam,  as  is 
ammonia,  but  the  ammonium  bases  or  quaternary  bases 
are  not  volatile. 


The  Nitriles  and  Amines  87 

The  above  described  reactions  for  the  formation  of  the 
primary,  secondary,  and  tertiary  bases  were  written  as 
if  only  one  product  was  formed  in  each  case,  e.g.  methyl- 
amine  from  methyl  halide  and  ammonia.  This  does  not 
represent  what  actually  takes  place,  however,  for  in  practice 
it  is  found  that  even  though  equimolecular  quantities  of 
these  two  substances  be  brought  into  reaction,  not  only 
is  methylamine,  which  is  the  principal  product,  produced, 
but  all  the  other  possible  methylamines,  as  well,  although 
in  much  smaller  amounts. 

44.  Separation  of  Amines  and  Ammonia.  —  Ammonia 
can  be  removed  quantitatively  from  its  mixtures  with 
the  amines  by  a  method  described  by  Erdmann.  The 
solution  containing  both  classes  of  compounds  (e.g.  the 
distillate  obtained  in  the  Kjeldahl  nitrogen  determina- 
tion) is  made  strongly  alkaline  with  a  mixture  of  sodium 
hydroxide  and  sodium  carbonate  and  yellow  mercuric 
oxide  (i.e.  the  oxide  in  a  very  fine  and  amorphous  state) 
added.  There  results  on  standing  a  reaction : 

2  HgO  +  NH3  =  Hg2N  -  OH  +  H2O 

The  alkyl  ammonias  or  amines  do  not  react  with  mer- 
curic oxide  in  this  way.  The  mercuric  ammonium  hy- 
droxide is  practically  insoluble  in  water  and  can  be  filtered 
off,  leaving  the  amines  in  solution. 

Delepine  has  proposed  a  method  for  separating  the 
primary,  secondary,  and  tertiary  amines  which  depends 
upon  the  fact  that  the  primary  and  secondary  con- 
dense with  formaldehyde,  while  the  tertiary  amines 
do  not : 


88    Organic  Chemistry  for  Students  of  Medicine 
CH3— NH2  +  HCHO  =  CH3— N  =  CH2  +  H2O 


Methyl-methylene  amine 
B.  P. '166° 

(CH3)2  =  NH  (CH3)2  =  N\ 

+  HCHO  =  CH2  +  H2O 

(CH3)2  =  NH  (CH3)2  =  N/ 

Methylene  derivative  of 

dimethylamine 

B.  P.  80-85° 

The  wide  difference  in  the  boiling  points  of  these  two 
compounds  makes  possible  their  separation.  The  bases 
can  be  regenerated  from  the  methylene  compounds  by 
hydrolysis. 

45.  Methods  of  Preparation. —  (1)  The  nitro  derivatives 
of  the  hydrocarbons  are  reduced  by  nascent  hydrogen,  yield- 
ing primary  amines : 

CH3— N02  +  6H  =  CH3— NH2  +  2  H2O 

(2)  The  nitriles,  including  hydrocyanic  acid,  can  take 
up  four  atoms  of  hydrogen,  passing  into  primary  amines : 

CHg— CN  +  4  H  =  CH3— CH2NH2 
HCN+4H=CH3— NH2 

(3)  Hydrolysis     of     alkyl    isocyanides    yields  primary 
amines  and  formic  acid  (40). 

(4)  The  action  of  alkyl  halides  on  ammonia  has  already 
been  referred  to  (43). 

(5)  The  oximes  (32)  are  reduced  by  nascent  hydrogen 
with  the  formation  of  primary  amines : 

CH3— CH  =  NOH  +4  H  =  CH3— CH2— NH2  +  H2O 

Acetaldoxime 

(6)  From  acid  amides  by  the  action  of  bromine  and 
sodium  hydroxide  (53). 


The  Nitriles  and  Amines  89 

46.  Isomerism  of  the  Amines.  — Two  types  of  isomers  of 
the  amines  should  be  mentioned.  One  is  like  the  isomer- 
ism  of  the  ethers,  viz.  metamerism.  Thus : 

/en, 

CHs— CH2—NH2  and  NH 

\CH3 

CH3\  CH3\ 

CH3— CH2— CH2— NH2  with         NH  and  with  CH3— N 

Propylamine  CH3— CH2/  CH3/ 

Methyl-ethyl  amine  Trimethylamine 

The  other  depends  upon  the  presence  of  normal  or 
branched  carbon  chains  as  in  the  alcohols  (9). 

Chemical  Behavior. —  (1)  The  amines  are  not  decom- 
posed by  saponifying  agents,  as  acid§  and  alkalies,  and 
are  oxidized  only  with  great  difficulty. 

(2)  A  reaction  which  distinguishes  the  primary  from 
the  secondary  and  tertiary  amines  is  their  behavior  with 
chloroform.     The  primary  amines  react  with  CHCla  and 
alcoholic    potassium   hydroxide,  with   the    formation   of 
isonitriles.     The  characteristic  odor  of  the  isonitriles  (40) 
serves  as  a  delicate  qualitative  test : 

CH3— NH2  +CHC13  +3  KOH 

=  CH3— N  =  C  +3  KC1  +3  H2O 

Methyl  isocyanide 

/ 

This  is  known  as  Hoffman's  carbylamine  reaction. 

(3)  Nitrous  acid  reacts  with  primary  amines,  replacing 
the   — NH2    group    by  hydroxyl,  — OH.       Elementary 
nitrogen  is  liberated  from  the  amino  group : 

— NH2  +  HONO  =  CH3OH  +  N2  +  H20 


90    Organic  Chemistry  for  Students  of  Medicine 

This  reaction  is  of  great  importance  in  synthetic  chemis- 
try, since  it  makes  possible  the  conversion  of  amines  into 
the  corresponding  alcohols. 

Recently  it  has  assumed  great  importance  in  the  eyes  of 
physiological  chemists  as  the  result  of  the  discovery  by 
Van  Slyke  of  the  conditions  necessary  for  making  this 
reaction  the  basis  of  a  simple  and  highly  accurate  quanti- 
tative estimation  of  amino  groups. 

With  the  secondary  amines  no  elementary  nitrogen  is 
formed  from  the  imino  group  =NH.  Instead  there  are 
formed  nitrosamines  : 


s^  3\ 

;NH  +  HONO  =       ;N—  NO 

CH/  CH3/ 

Dimethyl  nitrosamine 

Dimethyl  nitrosamine  is  an  oil  with  a  yellowish  color 
which  is  readily  volatile  with  steam  and  can  be  separated 
from  its  mixtures  in  this  way. 

Tertiary  amines  are  not  acted  upon  by  nitrous  acid. 

47.  Methylamine,  CH3  —  NH2,  occurs  in  Mercurialis 
perennis  and  in  the  distillate  from  bones  and  wood 
and  in  herring  brine  and  putrefaction  mixtures.  It  also 
appears  to  be  a  normal  constituent  of  urine,  but  in  very 
small  amounts.  It  is  a  gas  which  greatly  resembles  am- 
monia, but  its  odor  is  also  distinctly  fish-like.  It  is  even 
more  strongly  basic  than  ammonia.  Its  mixtures  with  air 
are  explosive,  and  it  burns  with  a  yellow  flame,  in  which 
it  differs  from  ammonia,  which  is  not  combustible.  One 
volume  of  water  dissolves  at  12.5°  1150  volumes  of  the  gas. 
It  precipitates  as  double  salts  the  salts  of  platinum  and 


The  Nitriles  and  Amines  91 

gold,  and  forms  methylated  ammonium  magnesium 
phosphate,  analogous  to  the  ammonium  magnesium  phos- 
phate. 

Methylamine  gives  with  Nessler's  reagent  (a  solution  of 
HgI2  and  KI  in  potassium  hydroxide)  a  precipitate  which  is 
insoluble  in  an  excess  of  the  reagent,  or  of  water.  This 
characteristic  serves  to  distinguish  it  from  the  secondary 
and  tertiary  amines. 

Dimethylamine  occurs  among  the  distillation  products 
of  wood  (pyroligneous  acid,  51)  and  in  guano.  It  boils 
at  7°. 

Trimethylamine,  (CH3)3N,  is  found  in  certain  plants, 
a,sChenopodium  vulvaria  and  Arnica  montana,  in  ergot,  and 
elsewhere.  It  is  a  decomposition  product  of  betaine  (63) 
and  similar  plant  bases  and  also  of  choline  (48),  and  results 
from  the  action  of  putrefactive  bacteria  on  materials  con- 
taining these  substances,  or  through  destructive  distilla- 
tion of  the  same,  as  in  the  distillation  of  vinasse.  Some 
investigators  have  reported  finding  traces  of  trimethyl- 
amine  in  urine,  but  in  the  light  of  recent  studies  with  im- 
proved methods  it  appears  that  fresh  normal  urine  of 
man  or  animals  does  not  contain  this  base.  It  has  an  odor 
resembling  ammonia,  but  also  fish-like.  It  boils  at  3.2°. 
Its  preparation  has  been  described  (43). 

Trimethylamine  breaks  up  when  strongly  heated,  form- 
ing methane  and  hydrocyanic  acid  : 

(CH3)3E=N  =  2  CH4  +  HCN 

Ethylamine,  CzKs — NH2,  is  formed  from  alanine  (69)  by 
destructive  distillation,  and  possibly  also  by  the  action  of 


92     Organic  Chemistry  for  Students  of  Medicine 

anaerobic  bacteria  on  the  same,  but  its  origin  through  the 
latter  agency  has  not  been  demonstrated.  It  has  little 
biological  importance. 

Oxyethylamine,  CH2OH  —  CH2  —  NH2,  has  been  found 
among  the  products  of  hydrolysis  of  lecithin  (96). 

Aside  from  those  mentioned  the  most  important  ali- 
phatic amines  are  the  following  : 


Isobutylamine,  /CH  —  CH2  —  NH2,    is    a    liquid 


which  boils  at  68°.  It  mixes  with  water  in  all  proportions. 
It  is  formed  by  putrefactive  bacteria  acting  on  amino 
isovalerianic  acid,  one  of  the  digestion  products  of  the 
proteins.  Its  formation  will  be  described  later  (73).  It 
differs  from  the  primary  amines  having  lower  alkyl  groups 
in  that  it  causes  a  rise  of  blood  pressure  in  animals. 


Isoamylamine,  /CH  —  CH2  —  CH2  —  NH2,  boils  at 


95°.  It  results  from  the  putrefaction  of  proteins,  being 
derived  from  the  amino  acid  leucine  (75)  ;  also  on  sterile 
self-digestion  (autolysis)  of  the  mushroom,  Boletm  edu- 
lus,  doubtless  formed  from  leucine.  When  intravenously 
injected  it  raises  the  blood  pressure.  With  hydrochloric 
acid  it  forms  a  salt,  isoamylamine  hydrochloride,  which 
is  employed  to  some  extent  as  an  antipyretic.  Both  the 
free  base  and  its  hydrochloride  are  soluble  in  water. 

48.  Choline  is  a  base  of  great  physiological  interest, 
since  it  occurs  in  all  cells  of  both  animals  and  plants  and 
is  especially  abundant  in  nervous  tissue.  It  does  not  occur 


The  Nitriles  and  Amines  93 

free  in  appreciable  amount  under  normal  conditions  in  the 
animal  body,  but  may  accumulate  in  the  cerebrospinal 
fluid  under  certain  pathological  conditions,  in  which 
degeneration  of  nervous  tissue  is  taking  place.  Choline  is 
always  a  constituent  of  certain  compounds  related  to  the 
fats,  called  lecithins  (96),  which  are  present  in  large 
amounts  in  brain  tissue  and  in  egg  yolk.  From  its  mode 
of  synthesis  it  is  shown  to  be  a  derivative  of  glycol  (22), 
and  trimethylamine.  It  is  formed  by  the  condensation  of 
trimethyl  ammonium  hydroxide  with  ethylene  oxide  (23). 

CH3\    /H          /CH2     CH2OH      nu 

CH3^N;     +o;  i    =|        /CHs 

CH3/    \OH       \CH2     CH2— N-CH3 

|\rH 
OHCH3 

Choline 

The  group  — CH2 — CH2OH  may  be  called  oxyethyl. 
The  name  of  choline,  considering  it  as  a  substituted  am- 
monium hydroxide,  is  trimethyl-oxyethyl-ammonium 
hydroxide. 

Choline  is  a  strong  base.  In  the  free  state  it  absorbs 
moisture  and  CC^  readily  from  the  air.  Its  solutions  may 
be  concentrated  by  boiling  to  4  %,  when  it  decomposes  into 
trimethylamine  and  glycol.  Choline  is  precipitated  by  a 
number  of  reagents,  the  most  efficient  being  potassium 
periodide,  which  precipitates  1  part  in  2,000,000  of  water. 

Choline  possesses  no  marked  physiological  action,  but 
by  the  action  of  bacteria  and  of  chemical  reagents  which 
abstract  water,  a  base  neurine  is  formed,  which  is  10-20 
times  more  toxic  than  is  choline  itself  (97). 


94     Organic  Chemistry  for  Students  of  Medicine 

Other  amines  of  physiological  importance  can  best  be 
described  in  their  relations  to  the  amino  acids. 

49.  Physiological  Action  of  the  Amines.  —  Whereas 
ammonia,  intravenously  injected,  produces  tetanic  con- 
vulsions, with  quickening  of  the  heart  and  respiration, 
the  amines  resulting  from  the  replacement  of  the  hydro- 
gen of  ammonia  by  the  aliphatic  hydrocarbons  have  but 
a  slight  physiological  action,  although  they  irritate  the 
mucous  membranes.  The  convulsant  effect  of  ammonia 
diminishes  progressively  as  the  hydrogen  atoms  are  suc- 
cessively substituted,  dimethylamine  being  less  toxic  than 
methylamine,  etc. 

When  the  tertiary  amines  pass  over  to  ammonium 
compounds,  i.e.  the  nitrogen  changes  from  the  trivalent 
to  the  pentavalent  state,  a  great  increase  in  toxicity  occurs. 
These  substances  resemble  many  of  the  alkaloids  in  their 
properties. 


CHAPTER   VI 
THE  FATTY  ACIDS 

50.  It  has  been  pointed  out  in  connection  with  the  alde- 
hydes (30,  31)  that  these  can  be  further  oxidized  to  acids  : 

R— CH2OH  +  02  =  R— COOH  +  H2O 

The  group  — ^\  QU  *s  called  carboxyl.  Its  — OH  com- 
plex behaves  like  a  unit  in  the  reaction  of  a  carboxyl  with 
the  chlorides  of  phosphorus,  the  resulting  compounds  being 
acid  chlorides  : 

3  CH3— COOH  +  PC13  =  3CH3— C/     +  H3PO3 

XC1 

Acetyl  chloride 

In  water  solution  the  organic  acids  give  the  tests  charac- 
teristic of  the  hydrogen  ion,  i.e.  they  are  acid  in  taste  and 
redden  blue  litmus,  and  change  the  color  of  numerous  dyes 
from  that  seen  in  their  alkaline  solutions.  The  compounds 
containing  the  carboxyl  group  conduct  the  electric  current 
as  do  the  inorganic  acids,  but  frequently  to  a  much  less 
extent,  since  many  of  them  are  to  be  classed  among  the 
weak  acids,  i.e.  they  dissociate  the  hydrogen  ion  to  but  a 
slight  extent. 

For  each  of  the  primary  alcohols  there  is  a  corresponding 
aldehyde  and  acid,  thus : 

95 


96     Organic  Chemistry  for  Students  of  Medicine 
R— CH2OH  --t-*  R— CHO  -^+  R— COOH 

Alcohol  Aldehyde  Acid 

The  acids  derived  from  the  aliphatic  hydrocarbons  are 
called  fatty  acids  because  most  of  them  are  found  as  esters 
in  the  fats  of  animals  and  plants.  The  lower  members 
of  the  series  are  liquids  of  pungent  odor  and  corrosive 
action.  They  boil  without  decomposition  and  are  readily 
soluble  in  water  and  behave  like  strong  acids. 

Formic  acid,  HCOOH,  is  the  lowest  member  of  the 
series.  It  occurs  free  in  ants  and  in  the  stings  of  some 
insects,  as  bees  and  caterpillars,  and  also  in  certain 
nettles,  in  the  fruit  of  the  soap  tree  (Sapindus  sapo- 
naria),  and  in  tamarinds  and  fir  cones.  It  is  always 
found  in  traces  in  perspiration  and  in  urine.  It  is  a 
colorless  liquid  with  a  pungent  odor.  At  20°  its  spe- 
cific gravity  is  1.221.  It  solidifies  in  a  freezing  mixture, 
melts  at  +  8.3°  and  boils  at  100.8°.  Formic  acid  is 
readily  soluble  in  water  and  in  many  organic  solvents. 
Its  vapors  are  combustible. 

It  is  the  strongest  acid  of  the  series,  being  dissociated 
into  H+  ions  to  about  twelve  times  the  extent  of  acetic 
acid.  It  produces  intense  irritation  of  the  skin  and  forms 
blisters. 

Formic  acid  does  not  behave  like  its  homologues  in  cer- 
tain respects.  It  is  easily  oxidized,  with  the  formation  of 
carbon  dioxide  and  water,  and  therefore  possesses  strong 
reducing  power,  depositing  mercury  and  silver  from  solu- 
tions of  their  oxides.  In  this  respect  it  has  the  properties 
of  an  aldehyde,  and  its  ready  decomposition  through  oxida- 


The  Fatty  Acids  97 

tion  probably  finds  its  explanation  in  the  acid  possessing 

jo 

the  formula  HO  —  Cf^     ,  or  hydroxy  formaldehyde. 

XH 
On  taking  up  oxygen  the  compound,  hydroxy  formic 

acid  containing  two  hydroxy  Is,  HO  —  C^      ,  is  formed. 

XOH 

Two  hydroxyls  cannot  remain  attached  to  a  single  carbon 
atom,  however,  except  in  a  few  circumstances  (see  chloral), 
and  water  is  immediately  separated  with  the  liberation  of 
carbon  dioxide  : 


HO—  C  =  CO2  +  H2O 

\OH 

Formation.  —  (1)  Formic  acid  is  obtained  by  the  oxida- 
tion of  methyl  alcohol  : 

CH3—  OH  +2O  =  HCOOH  +  H2O 

(2)  Hydrocyanic   acid,  HCN,  behaves  as  a  nitrile   in 
that  it  can  take  up  two  molecules  of  water,  forming    the 
ammonium  salt  of  formic  acid  : 

HCN  +  2H2O  =  HCOONH4 

From  the  ammonium  salt  free  formic  acid  can  be  ob- 
tained by  treatment  with  a  nonvolatile  acid  and  distilling  : 

2  HCOONH4  +  H2SO4  =  2  HCOOH  +  (NH4)2SO4 

(3)  Carbon  monoxide  gas,  CO,  reacts  with  the  caustic 
alkalies  : 

CO  +  KOH  =  HCOOK 

Potassium  formate 


98     Organic  Chemistry  for  Students  of  Medicine 

Chemical  behavior.  —  (1)  The  above  reaction  serves  as 
another  example  of  the  passage  of  carbon  from  the  divalent 
to  the  tetravalent  state  (40).  At  169°  formic  acid  is  again 
dissociated  into  water  and  carbon  monoxide  : 


O  =  CH  ->  CO  +  H20 

Formic  acid 

indicating  that  at  high  temperatures  the  carbon  in  certain 
complexes  tends  to  become  spontaneously  divalent. 

(2)  On  strongly  heating  the  alkali  formates  with  alkali 
hydroxide  they  are  decomposed  into  alkali  carbonate  and 
hydrogen  :      HCOOK  +  KOH  =  K2CO3  +  H2 

(3)  The  alkali  formates  when  heated  to  about  400° 
decompose  into  oxalic  acid  and  hydrogen  : 

COOK 

2HCOOK  =|  +H2 

COOK 

(4)  Formic  acid  can  be  transformed  back  into  its  nitrile, 
HCN,  by  heating  its  ammonium  salt  above  its  melting 
point.     As  an  intermediary  product,  formamide  (53),  is 
produced  : 

HCOONH4  ~H2°>  HCONH2   ~H2°>  HCN 

Ammonium  formate  Formamide 

(5)  Concentrated    sulphuric   acid   withdraws   the   ele- 
ments of  water  from  formic  acid,  liberating  carbon  mon- 
oxide :  HCOOH  =  H2O  +  CO 

Of  the  salts  of  formic  acid  most  are  readily  soluble. 
Mercury    formate,    (HCOO)2Hg,    and    silver    formates, 


The  Fatty  Acids  99 

Ag(HCOO),  are  difficultly  soluble,  but  are  readily  decom- 
posed on  warming.  Lead  formate,  Pb(HCOO)2,  is  soluble 
in  63  parts  of  water  at  16°  and  in  5.5  parts  at  100°.  Zinc 
formate,  Zn(HCOO)2,  is  insoluble  in  alcohol,  a  property 
which  distinguishes  it  from  the  zinc  salts  of  its  volatile 
homologues,  acetic,  butyric,  etc. 

(6)  The  reduction  of  the  heavy  metals  by  formic  acid 
may  be  illustrated  by  the  decomposition  of  the  silver  and 
mercuric  salts : 

2  HCOOAg  =  HCOOH  +  CO2  +  2  Ag 
2  (HCOO)2Hg  =  HCOOH  +  CO2 '+  2  HCOOHg 

Mercuric  formate  Mercurous  formate 

(7)  A  qualitative  test  for  formic  acid  which  is  of  great 
delicacy  rests  on  the  formation  of  carbon  monoxide  gas  on 
heating  with  concentrated   sulphuric  acid.     The  gas  is 
passed  into  a  dilute  solution  of  blood  and  the  latter  is 
then   examined    spectroscopically   for   the   characteristic 
spectrum  of  carbon  monoxide  haemoglobin. 

(8)  A  property  of  formic  acid  of  great  interest  biologi- 
cally is  that  of  spontaneously  decomposing  into  hydrogen 
and  carbon  dioxide  in  the  presence  of  metallic  rhodium : 

HCOOH  ->  H2  +  C02 

The  attempt  has  been  made  to  explain  the  mechanism  of 
fermentation  on  the  assumption  that  yeast  produces  an 
organic  catalyst  which  effects  this  decomposition  (see 
Fermentation,  164). 

51.  Acetic  acid,  CH3COOH,  is  the  acid  found  in  vine- 
gar, where  it  is  derived  by  the  fermentation  of  glucose 


100     Organic  Chemistry  for  Students  of  Medicine 

into  alcohol  and  the  subsequent  oxidation  of  the  alcohol 
through  aldehyde  to  acid  : 

+  0  +0 

CH3— CH2OH  -*  CH3— CHO  ->  CH3COOH 

Its  formation  is  the  cause  of  the  souring  of  beer,  wine, 
and  cider.  Cider  vinegar  contains  small  amounts  of 
alcohol  and  of  acids  other  than  acetic  (tartaric,  succinic, 
etc.)  and  also  ethyl  esters  of  these  acids,  and  to  these 
it  owes  its  flavor.  It  contains  usually  but  3  to  5  % 
of  acid.  The  acid  volatilizes  readily,  and  in  order  to 
obtain  it  in  a  pure  form  from  its  dilute  solutions  it  is  con- 
verted into  a  salt  which,  being  non-volatile,  can  be  heated 
to  evaporate  the  water.  The  salt  is  finally  treated  with 
hydrochloric  acid,  avoiding  an  excess,  and  the  mixture 
distilled,  when  strong  acetic  acid  passes  over : 

(CH3— COO)2Ca  +  2  HC1  =  2  CH3— COOH  +  CaCl2 

Pyroligneous  Acid.  —  When  hardwoods  are  heated  in  a 
distilling  apparatus,  a  tarry  product  containing  carbolic 
acid  and  related  substances  is  formed,  and  there  distills 
over  a  gaseous  mixture  containing  hydrogen,  methane, 
carbon  monoxide,  and  carbon  dioxide,  a  moderate  amount 
of  higher  hydrocarbons  (7  %),  and  a  mixture  of  water, 
methyl  alcohol,  acetone,  and  acetic  acid,  together  with 
numerous  other  compounds  in  small  quantities  as  im- 
purities. This  mixture  is  known  as  pyroligneous  acid. 
Methyl  alcohol  and  acetone  are  so  readily  volatile  that 
they  can  be  distilled  from  the  dilute  acetic  acid,  thus  effect- 


The  Fatty  Acids  101 

ing  a  partial  separation.  The  acetic  acid  is  then  neutral- 
ized with  lime,  forming  calcium  acetate,  Ca(OOC — CH3)2, 
and  the  latter  is  then  heated  to  200°  in  contact  with  air 
to  oxidize  the  tarry  matters.  From  this  crude  calcium 
acetate  the  acetic  acid  is  obtained. 

In  marked  contrast  to  formic  acid,  acetic  acid  is  extraor- 
dinarily resistant  to  oxidation.  It  is  not  oxidized  by 
chromic  acid  under  any  ordinary  conditions  and  can  be 
passed  through  a  glowing  tube  without  decomposition. 
It  is  not  oxidized  by  dilute  solutions  of  potassium  per- 
manganate, which  quickly  decompose  formic  acid.  Silver 
acetate  in  water  solution  can  be  heated  without  reduc- 
tion (blackening)  taking  place. 

It  is  this  great  stability  which  explains  why  acetic  acid 
occurs  in  such  large  quantities  in  the  pyroligneous  acid. 
During  the  decomposition  of  the  various  complex  com- 
pounds (cellulose,  lignin,  pentosans,  etc.)  numerous  de- 
composition products  are  formed  which,  being  unstable  at 
high  temperatures,  are  further  decomposed,  and  in  the 
end  only  the  most  stable  products  remain.  Numerous 
compounds  on  oxidation  yield  acetic  acid,  and  owing  to  its 
great  stability  the  reaction  stops  at  this  point. 

Even  the  animal  body  possesses  but  a  very  limited 
capacity  to  oxidize  acetic  acid.  Normal  human  urine 
contains  from  60  to  280  mgm.  of  acetic  acid  per  day. 

Acetic  acid,  despite  its  stability,  is  readily  fermented 
in  the  form  of  its  calcium  salt  by  certain  organisms  into 
methane  and  carbon  dioxide  : 

CH3— COOH  =  CH4  +  CO2 


102     Organic  Chemistry  for  Students  of  Medicine 

Calcium  acetate  when  heated  in  the  dry  condition  to  the 
point  of  decomposition  yields  acetone  and  calcium  car- 
bonate : 

CH3 


\      ;Ca  =  CO   +CaCO3. 
CH3—  CCfcK  | 

CH3 

This  type  of  decomposition  is  common  to  the  higher 
fatty  acids  and  is  therefore  a  general  method  of  preparing 
ketones.  When  the  salts  of  two  different  acids  are  em- 
ployed, mixed  ketones  result  : 

CHs—  COOca  +  CH3—  CH2—  COOca 

f  Calcium  propionate 

->  CH3—  CO—  CH2—  CH3     (ca  =  *  Ca) 

Methyl  -ethyl-ketone 

Glacial  Acetic  Acid.  —  When  nearly  free  from  water  acetic 
acid  solidifies  when  cooled  below  16.7°  to  a  crystalline 
mass,  from  which  it  derived  its  name,  glacial  acetic  acid. 
It  boils  at  118°  and  has  a  specific  gravity  of  1.055  at  15°. 
When  mixed  with  water,  contraction  and  increase  in  den- 
sity ensue,  the  maximum  change  taking  place  when  equal 
molecules  of  water  and  acetic  acid  are  combined.  This 
solution  contains  76  per  cent  acid  and  at  15°  has  a  specific 
gravity  of  1.075.  On  further  dilution  the  specific  gravity 
decreases  until  a  50  per  cent  solution  has  nearly  the  same 
density  as  has  the  glacial  acid.  It  is  therefore  impossible 
to  employ  the  specific  gravity  as  an  index  to  the  strength 
of  this  acid.  This  is  obtained  by  titration  with  a  standard 
solution  of  an  alkali  employing  an  indicator. 


The  Fatty  Acids  103 

Tests  for  acetic  acid :  (1)  The  odor  of  acetic  acid  is  ex- 
traordinarily characteristic  and  easily  recognizable. 

(2)  When  acetic  acid  or  an  acetate  is  treated  with  alco- 
hol and  sulphuric  acid,  the  characteristic  odor  of  ethyl 
acetate  is  obtained. 

(3)  From  concentrated  solutions  silver  nitrate  precipi- 
tates the  white,  difficultly  soluble  silver  acetate,  which 
contains  64.65  per  cent  of  silver. 

52.  The  Acid  Chlorides.  —  The  fatty  acids  are  acted 
upon  by  the  trichloride  of  phosphorus  with  the  replace- 
ment of  hydroxyl  by  chlorine,  the  resulting  compounds 
being  known  as  acid  chlorides  : 

3  CH3— COOH  +  PC13  =  3  CH3COC1  +  H3PO3 

Acetyl  chloride 

It  is  a  liquid  with  a  suffocating  odor,  which  boils  at  51°, 
specific  gravity  1 . 138  at  0°.  It  fumes  in  the  air  owing  to  its 
reaction  with  the  moisture  therein.  It  decomposes  vio- 
lently with  water,  forming  acetic  and  hydrochloric  acids : 

CH3— COC1  +  HOH  =  CH3— COOH  +  HC1 
With  alcohols  it  reacts  to  form  esters : 
CH3COC1  +  HOCH2— CH3  =  CH3— COOC2H5  +  HC1 

Ethyl  acetate 

This  reaction  is  one  of  great  importance  in  determining 
the  presence  and  number  of  hydroxyl  groups  which  are 
contained  in  a  compound  under  investigation.  The  ester 
is  produced  according  to  the  above  reaction.  This  is  a 
neutral  compound  and  can  be  separated  from  the  excess 
of  acetyl  chloride  by  treatment  with  water.  A  measured 
quantity  of  the  acetyl  compound  (ester)  is  then  treated 


104     Organic  Chemistry  for  Students  of  Medicine 

with  a  known  volume  of  standardized  alcoholic  potassium 
hydroxide  and  heated  until  the  ester  is  completely  hy- 
drolysed,  i.e.  reconverted  into  acetic,  acid  and  alcohol. 
From  the  amount  of  alkali  used  up  in  neutralizing  the 
acetic  acid  which  was  formed  in  the  hydrolysis  the  number 
of  hydroxyl  groups  can  be  estimated. 

53.  The  Acid  Amides.  —  The  amides  may  be  regarded 
as  organic  acids  in  which  the  hydroxyl  of  the  carboxyl 
group  is  replaced  by  the  amino  group,  — NH2 : 

S°  ^°  ^° 

R— C<  R— Cf .  R— C<f 

XOH  XC1  XNH2 

Acid  Acid  chloride  Acid  amide 

The  amides  are  formed  in  several  ways  which  illustrate 
their  relationship  to  other  classes  of  compounds : 

(1)  Acid  chlorides  react  with  ammonia,  forming  hydro- 
chloric acid  and  amide : 

CHa— COC1  +  2NH3  =  CH3— CONH2  +  NH4C1. 

Acetamide 

If  substituted  ammonias  (amines)  are  employed  for 
ammonia,  alkylated  amides  result : 

GHa— COC1  +  2  NH2— CH3  =  CH3— CO— NHCH3 

Methylamine  Methyl  acetamide 

+  CHs— NH3C1 

Methyl-ammonium  chloride 

(2)  The  alkyl  nitriles  react  with  one  molecule  of  water, 
forming  acid  amides : 

CH3CN  +  H2O  =  CH3— CO— NH2 

This  reaction  is  the  first  step  in  the  formation  of  acid 
from  nitrile.  The  amides  take  on  a  second  molecule  of 


The  Fatty  Acids  105 

water,  passing  into  the  ammonium  salts  of  the  correspond- 
ing acids  (50). 

Strong  dehydrating  reagents,  such  as  phosphorus  pen- 
toxide,  can  abstract  from  the  acid  amides  a  molecule  of 
water  with  the  regeneration  of  nitriles : 

3  CH3— CO— NH2  +P2O5  =  3  CH3— CN  +  2  H3PO4 

In  order  to  effect  the  addition  of  one  molecule  of  water 
only,  the  nitriles  are  treated  with  some  reagent  which  con- 
tains water,  but  which  has  a  strong  affinity  for  the  latter 
(e.g.  strong  sulphuric  or  hydrochloric  acid). 

(3)  By  the  dry  distillation  of  the  ammonium  salts  of  the 
fatty  acids,  or  by  heating  them  in  a  closed  tube  to  230°, 
water  is  separated  with  the  formation  of  the  amide : 

CHs— COONH4  =  CH3— CO— NH2  +  H2O 

(4)  Esters  can  react  with  ammonia  with  the  production 
of  amides  and  alcohols: 

CH3— COOC2H5  +  NH3  =  CH3— CO— NH2  +  C2H5OH 

The  amides,  being  derivatives  of  ammonia,  which  is 
strongly  basic,  formed  by  the  exchange  of  one  hydrogen 
for  an  acid  radical,  possess  very  feeble  basic  properties. 
Thus  acetamide  forms  a  salt  with  hydrochloric  acid,  which 
is  however  very  easily  decomposed  by  water.  Acetamide 
hydrochloride  is  formed  when  dry  hydrochloric  acid  gas  is 
passed  into  an  ethereal  solution  of  acetamide. 

On  the  other  hand  the  hydrogen  of  the  NH2  group  in  the 
acid  amides  behaves  like  acid  hydrogen.  An  aqueous 
solution  of  acetamide  dissolves  mercuric  oxide,  forming  a 
compound  analogous  to  the  salts  : 


106     Organic  Chemistry  for  Students  of  Medicine 

CHg—  CO—  NH 


2  CHa—  CO-NH2  +  HgO  = 


+  H2O 


CH3—  CO—  NH 


The  relationships  and  mutual  transformations  among 
the  compounds  of  the  types  thus  far  considered,  excluding 
the  ethers  and  esters,  are  shown  by  the  following  scheme. 
The  series  includes  some  compounds  which  will  be  con- 
sidered immediately  : 


CH3  CH3       +0 

AgOH 

CH2OH  H 


:OOH      COOH 

|AgOH 
0 


* 


CH2OH 


m 


H 


OOH 


CH2OH  /^ 


CHO 


COOH 


_O 
if 


COOH 


COOH 


CHO 


O 


^CH2OH 

"I 
CH2OH 


The  Fatty  Acids  107 

54.  Halogen  Derivatives  of  Acetic  Acid.  —  When 
chlorine  or  bromine  acts  upon  acetic  acid  a  substitution 
of  hydrogen  by  halogen  takes  place.  The  resulting 
products  may  be  mono-,  di-,  or  trichloracetic  acid  depend- 
ing on  the  extent  of  the  substitution. 

Chloracetic  acid,  CH2C1— COOH,  melts  at  62.5°.  It 
exerts  a  corrosive  action  similar  to  that  of  glacial  acetic 
acid  on  the  skin,  and  the  vapors  are  highly  irritating. 

Dichloracetic  acid,  CHC12— COOH,  melts  at  -  4°. 
Its  chief  interest  is  its  usefulness  in  syntheses  of  other 
compounds. 

Trichloracetic  acid,  CC13— COOH,  is  a  solid,  M.  P. 
80°.  It  is  extremely  caustic  in  its  action  on  the  skin,  and 
is  employed  for  the  removal  of  warts,  corns,  and  similar 
growths.  It  is  likewise  employed  as  a  precipitant  for 
proteins,  with  which  it  forms  compounds  which  are  rela- 
tively insoluble  in  water  or  dilute  acids. 

The  acidity  of  the  chlorinated  acetic  acids,  i.e.  the  de- 
gree of  dissociation  of  hydrogen  ions,  increases  with  increas- 
ing chlorine.  All  are  stronger  acids  than  acetic.  The 
strength  of  trichloracetic  acid  ranks  it  with  the  strong 
mineral  acids. 

With  fatty  acids  containing  three  or  more  carbon  atoms 
chlorine  or  bromine  react  to  form  halogen  substituted 
acids.  In  all  cases  the  hydrogen  substituted  is  one  bound 
to  the  carbon  atom  neighboring  the  carboxyl  group.  This 
is  designated  the  alpha  carbon  atom  and  is  usually  abbre- 
viated a.  Thus : 

CH3— CH2— COOH+2C1  =  CH3— CHC1— COOH+HC1 

Propionic  acid  tt-chlorpropionic  acid 


108     Organic  Chemistry  for  Students  of  Medicine 

The  successive  carbon  atoms  of  the  fatty  acids  are 
'designated  by  the  letters  of  the  Greek  alphabet,  in  order 
of  their  position,  with  respect  to  the  carboxyl  group. 

Thus:       .  .  .  CH2-CH2— CH2-CH2-COOH 

5  7  £  « 

55.  The  Hydroxy  Acids.  —  With  water  on  prolonged 
boiling  the  alpha-halogen  acids  react  with  the  replacement 
of  halogen  by  hydroxyl.  The  exchange  is  greatly  facili- 
tated by  the  presence  of  silver  oxide. 

CH2C1  CH2OH 

+  HOH=   |  +HC1 

COOH  COOH 

Chloracetic  acid  Glycolic  acid 

Glycolic  acid  is  of  interest  from  the  biological  standpoint. 
It  may  be  regarded  as  an  oxyacetic  acid.  It  is  found  in 
unripe  grapes,  in  sugar  cane,  and  in  many  other  plants, 
especially  in  the  green  parts.  It  is  taken  internally  there- 
fore with  the  food  to  a  slight  extent.  It  is  somewhat  toxic 
in  large  doses.  It  is  a  crystalline  compound,  M.  P.  80°, 
easily  soluble  in  water,  alcohol,  and  ether,  but  difficultly 
in  acetone.  It  does  not  appear  in  the  urine  after  adminis- 
tration, but  has  been  found  after  the  ingestion  of  glycol. 
It  is  a  possible  intermediary  product  of  the  oxidation  of 
certain  complex  foodstuffs  in  the  course  of  metabolism. 
Its  relation  to  alcohol  and  glycol,  from  which  it  is  formed 
by  oxidation,  is  seen  from  the  following  formulae : 

CH3  CH3         CH3  CH2OH 


O 


O 


O 


CH2OH          CHO       COOH        COOH 

Ethyl  alcohol      Acetaldehyde      Acetic  acid  Glycolic  acid 


The  Fatty  Acids  109 

CH2OH  CHO  CHO 


0 


o 


CH2OH  CH2OH         COOH 

Glycol  Glycol  aldehyde      Glyoxylic  acid 

On  further  oxidation  it  yields  a  compound  called  gly- 
oxylic  acid,  which  is  at  the  same  time  both  an  acid  and 
an  aldehyde. 

Glyoxylic  acid  is  in  turn  in  conformity  with  its  aldehyde 
nature  oxidized  to  oxalic  acid  (100)  which  contains  two 
carboxyl  groups : 

CHO  COOH 

O 

COOH  COOH 

Oxalic  acid 

56.  The  Amino  Acids.  —  Not  only  can  a  hydrogen  atom 
of  the  methyl  group  of  acetic  acid  be  replaced  by  halogen, 
hydroxyl,  or  alkyl  group,  but  also  by  the  amino  group 
— NH2,  with  the  formation  of  amino  acids.  In  respect  to 
halogen,  hydroxyl,  and  amino  derivatives,  formic  acid 
behaves  very  differently  from  its  homologues,  acetic, 
propionic,  etc.,  acids.  Thus  chlor  formic  acid  C1COOH  is 
incapable  of  existence  in  the  free  state,  but  its  esters  are 
known.  Thus  COC12,  which  is  to  be  regarded  as  the  acid 
chloride  of  chlor  formic  acid,  reacts  with  alcohols  to  form 
chlor  formic  esters : 

Cl— CO— Cl  +  HOC2H5  =  Cl— COOC2H5  +  HC1 

Chlor  formic  esters 

The  chlor  formic  esters  behave  like  acid  chlorides,  how- 
ever, in  that  they  are  decomposed  by  water. 


110     Organic  Chemistry  for  Students  of  Medicine 

Carbamic  Acid. —  The  ammonium  salt  of  amino-formic 
acid,  or  carbamic  acid,  is  formed  when  ammonia  gas 
reacts  with  carbon  dioxide  : 

2NH3  +  CO2  =  NH2— COONH4 

Ammonium  carbamate 

Ammonium  carbamate  is  present  as  an  impurity  in 
commercial  ammonium  carbonate.  On  treatment  of 
NH2 — COONH4  with  a  mineral  acid  it  is  at  once  decom- 
posed with  evolution  of  carbon  dioxide  : 

NH2— COONH4  +  HC1  =  NH4C1  +  NH2— COOH 
NH2— COOH  =  CO,  +  NH3 

The  metallic  salts  of  carbamic  acid  are  more  stable,  but 
decompose  at  ordinary  temperatures  in  solution  into  car- 
bonates : 

NH2— COOK  +  H2O  =  NHa  +  KHCO3 

Carbamic  acid  is  distinguished  from  carbonic  acid  in  the 
solubility  of  certain  of  its  salts.  Solutions  of  sodium  or 
potassium  carbamate  give  no  precipitate  with  calcium 
chloride,  as  do  the  corresponding  carbonates. 

The  alkali  salts  of  carbamic  acid  lose  water  on  heating 
to  redness  and  pass  into  the  cyanates : 

NH2— COOK  =  KCNO  +  H2O 

Ammonium  carbamate  is  an  intermediary  compound  in 
the  formation  of  urea  in  the  living  tissues.  Ammonium 
carbamate  on  the  abstraction  of  a  molecule  of  water  forms 
the  amide  of  carbamic  acid,  or  carbamide,  the  popular  name 
for  the  latter  being  urea,  a  name  which  was  given  to  the 


The  Fatty  Acids  111 

principal  nitrogenous  compound  in  the  urine  of  mammals 
before  the  development  of  the  science  of  organic  chemis- 
try: 

NH2—  COONH4  =  NH2—  CO—  NH2  +  H2O 

Urea 

This  structure  of  urea  is  further  confirmed  by  its  forma- 
tion from  carbon  oxy  chloride  and  ammonia  : 

/Cl     HNH2  /NH2 

C0(       +  =CO  +2HC1 

\C1     HNH2 


Urea  is  likewise  produced  by  a  rearrangement  of  the 
atoms  within  the  molecule  of  ammonium  isocyanate 
when  the  latter  is  heated  above  its  melting  point  : 


Rearrangement         / 
NH4OCN >  C0( 


NH5 


This  transformation  was  observed  by  Wohler  in  1828 
and  was  the  first  synthesis  of  an  organic  compound.  The 
change  of  ammonium  isocyanate  into  urea  is  never  quite 
complete,  for  a  condition  is  reached  where  a  definite  pro- 
portion between  the  isocyanate  molecules  and  urea  mole- 
cules exists.  The  reaction  is  reversible.  When  silver 
nitrate  is  added  to  a  solution  of  pure  urea,  silver  isocyanate 
is  precipitated.  The  amount  of  isocyanate  present  in 
such  solutions  is,  however,  extremely  small,  but  if  removed 
by  the  formation  of  an  insoluble  compound  the  reaction 
proceeds  in  the  direction  which  leads  to  its  formation. 
In  certain  reactions  urea  behaves  as  if  it  had  the  struc- 


112    Organic  Chemistry  for  Students  of  Medicine 


^ 

ture  C  —  OH.     Thus    methyl    alcohol    condenses    with 
\NH2     . 


cyanamid  Cv  to  form  methyl  isourea: 

\ 


/OCH3 

+  HOCH3  =  C=NH. 
\NH2 

The  structure  is  proven  by  the  fact  that  on  heating  this 
compound  with  hydrochloric  acid  (hydrolysis)  methyl 
chloride  is  formed.  From  methylurea,  which  is  formed 
when  the  salt  of  cyanic  acid  with  methylamine  (methyl 
ammonium  cyanate)  is  heated  alone,  there  results,  on 
hydrolysis  with  hydrochloric  acid,  methylamine  : 

Rearrangement       /NHCH3 
CH3NH2  -  HOCN  -  -  -  >CO( 

\NH2 

Methyl  urea 

CH3NH2 
-  >C02  + 
+  H2O  NH3 

In  isomethyl  urea  the  methyl  group  cannot  be  linked  to 
nitrogen. 

When  heated,  urea  melts  and  at  a  higher  temperature 
begins  to  evolve  gas,  consisting  of  ammonia  and  carbon 
dioxide.  The  melt  finally  solidifies.  There  are  several 
types  of  decomposition  which  take  place,  the  principal 
ones  being  the  formation  of  biuret  and  cyanuric  acid. 

(1)  NH2—  CO—  |  NH2     H  |  HN—  CO—  NH2 

=  NH2—  CO—  NH—  CO—  NH2  +  NH3 

Biuret 


The  Fatty  Acids  113 


(2) 


HJHN— CO— NH— CO— NHf 


H2N  —  CO—  NH2 


/CO— NHV 

=  NH(  )CO  +  2NH3. 

\CO— NH/ 

Cyanuric  acid 

The  reactive  form  of  cyanuric  acid  is  probably  not  that 
indicated  by  the  above  formula.  It  is  a  tribasic  acid,  and 
forms  salts,  indicating  the  presence  of  three  acid  hydrogens. 
It  is  best  represented  by  the  following  structural  formula : 

/OH 


57.  Urea  is  one  of  the  longest  known  of  organic  com- 
pounds. It  constitutes  85-90  %  of  the  nitrogen  of  normal 
human  urine.  The  average  amount  of  urea  eliminated 
daily  by  a  man  on  an  ordinary  diet  is  about  30  grams.  The 
amount  may  vary  greatly  with  the  character  of  the  diet, 
being  high  when  much  protein  is  eaten  and  low  when  the 
protein  intake  is  low.  It  is  a  neutral  substance,  forming 
crystals  which  melt  at  130-132°;  very  soluble  in  water 
(1:1)  and  in  alcohol  (1 :  5  of  cold  alcohol),  but  insoluble  in 
ether  and  chloroform. 

Urea  is  a  neutral  substance  with  respect  to  indicators, 
but  acts  as  a  feeble  base  in  that  it  forms  salts  with  acids. 
Urea  nitrate,  CO(NH2)2  •  HNOs,  is  a  crystalline  compound 
soluble  in  water,  but  slightly  soluble  in  nitric  acid.  It  is 


114     Organic  Chemistry  for  Students  of  Medicine 

slightly  soluble  in  alcohol,  but  easily  in  acetone.  It  is 
employed  for  the  isolation  of  urea  from  urine.  The  salt 
is  decomposed  by  barium  carbonate : 

2  CO(NH2)2  •  HN03  +  BaC03    =   Ba(N03)2  +  C02    + 

NH2 
H20 


The  urea  is  separated  from  Ba(NQ3)2  by  solution  in 
alcohol.  Urea  forms  salts  with  other  acids,  the  most 
important  being  that  with  oxalic  acid,  [CO(NH2)2]2C2H2O4. 
This  is  a  crystalline  compound  soluble  in  water,  but  nearly 
insoluble  in  oxalic  acid  solutions,  slightly  soluble  in  alcohol. 
It  is  also  employed  for  the  isolation  of  urea  from  urine. 

Urea  also  forms  a  compound  with  mercuric  nitrate  and 
mercuric  oxide  of  the  formula : 

2  CO(NH2)2  -  Hg(NO3)2  -  3  HgO 

It  likewise  forms  a  compound  with  mercuric  oxide, 
CO(NH2)2HgO. 

Urea  in  moderate  concentration  possesses  no  appre- 
ciable toxicity  for  the  higher  animals,  but  is  much  more 
toxic  to  birds.  The  latter  do  not  excrete  their  waste 
nitrogen  as  urea,  but  principally  as  ammonium  urate  (147). 
Even  in  so  great  dilution  as  i  %  solutions,  urea  is 
noticeably  toxic  to  certain  plants.  Certain  bacteria  can 
employ  urea  as  a  source  of  energy,  although  it  yields  very 
little  energy  on  decomposition.  The  change  which  takes 
place  in  urea  fermentation  is  as  follows : 

CO(NH2)2  +  H2O  =  COg  +  2  NH3  +  102  Calories 


The  Fatty  Acids  115 

Since  the  fermentation  always  takes  place  in  solution,  the 
products  of  the  decomposition  unite  with  water  to  form 
ammonium  carbonate.  This  decomposition  of  urea  is 
brought  about  by  an  enzyme  or  organic  catalyzer  produced 
by  the  microorganisms.  It  has  recently  been  discovered 
that  this  enzyme,  which  is  called  urease,  is  present  in 
liberal  amounts  in  certain  beans,  notably  the  Jack  bean 
and  the  Soy  bean.  When  an  extract  of  the  beans  is 
added  to  a  solution  of  urea  and  the  mixture  protected  from 
bacterial  action  by  toluene,  the  transformation  of  urea  into 
ammonium  carbonate  takes  place  rapidly  and  is  complete 
within  a  few  hours  at  favorable  temperatures.  The  am- 
monia is  titrated,  employing  methyl  orange  as  indicator, 
either  directly  or  after  aspirating  it  into  a  solution  of 
standard  acid.  This  method  was  first  described  by 
Marshall. 

The  quantitative  estimation  of  urea  by  the  Folin-Benedict 
method  is  effected  by  converting  it  into  COg  and  NH3  by 
heating  the  acidified  urine  in  an  autoclave.  The  resulting 
ammonia  is  removed  by  a  current  of  air  and  is  absorbed 
by  a  measured  quantity  of  standard  acid.  A  separate 
determination  of  ammonia  is  made  on  an  unheated  sample 
and  the  result  subtracted  from  that  obtained  with  the 
heated,  the  difference  representing  urea. 

58.  Thiourea  is  formed  from  ammonium  isothiocyanate 
on  treating  in  a  manner  analogous  to  the  formation  of  urea 
from  ammonium  isocyanate : 

/NH2 
NH4SCN  — - 


116     Organic  Chemistry  for  Students  of  Medicine 

Thiourea  crystallizes  readily  in  very  large  crystals. 
It  is  readily  soluble  in  water  but  insoluble  in  alcohol.  It 
melts  at  172°.  It  exhibits  the  behavior  of  existing  in  the 
tautomeric  form  in  part,  for  on  treatment  with  alkyl 
iodide  it  forms  alkyl  thioureas  which  possess  the  pseudo 
form,  the  alkyl  group  being  linked  to  sulphur  instead  of 

nitrogen  : 

/NH2  /NH2 

C—  SH  +  IC2H5  =  C—  S—  C2H5  +  HI 


Thiourea  Pseudo-ethyl-thiourea 

That  the  alkyl  group  is  linked  to  sulphur  is  shown  by  its 
decomposition  into  ethyl  mercaptan  instead  of  ethyl 
amine,  as  it  would  were  the  ethyl  group  linked  to  nitrogen 
(57).  When  treated  with  mercuric  oxide  thiourea  loses 
hydrogen  sulphide  and  forms  cyanamide  : 

NH2  NH2 


/I 

^N 


SH 
H 


C       +H2S 


N 


59.  Esters  of  Carbamic  Acid.  —  Carbon  oxychloride, 
COC12,  which  is  formed  by  the  direct  union  of  carbon 
monoxide  and  chlorine  in  sunlight,  can  react  with  alcohol 
to  form  the  ethyl  ester  of  chlor  formic  acid : 

d— CO— Cl  +HOC2H6  =  Cl— CO— OC2H5  +HC1 

Chlor  formic  ester 

Chlor  formic  ethyl  ester  is  a  volatile  liquid  of  very  pun- 
gent odor  which  boils  at  93°.  It  reacts  like  an  acid  chloride, 
being  decomposed  by  water. 


The  Fatty  Acids  117 

60.  Urethanes.  —  Chlor  formic  ester  reacts  with  am- 
monia to  form  amino  ethyl  formate,  the  ethyl  ester  of  amino 
formic  acid.     This  compound  is  called  ur ethane: 

/C\  //NH2 

CO  +NH3=CO  +  HC1 

\OC2H5  \OC2H5 

Urethane  is  a  colorless  crystalline  substance  possessing  a 
faint  peculiar  odor  and  a  taste  somewhat  like  that  of 
potassium  nitrate.  It  is  soluble  in  0.6  parts  of  alcohol, 
1  part  of  water,  1  part  of  ether,  and  in  3  parts  of  glycerol. 
It  melts  at  48-50°  and  boils  at  180°.  It  is  employed  as 
a  sedative  and  hypnotic.  A  number  of  derivatives  of 
urethane  have  been  introduced  as  hypnotics  and  sedatives 
in  the  quest  for  those  which  possess  the  most  advantageous 
properties.  Among  these  may  be  mentioned : 

Hedonal  is  an  ester  of  carbamic  acid  with  the  amyl 
alcohol,  methyl  propyl  carbinol : 

/NH, 
CO     /CH3 
\OCH- CH2—CH2— CH3 

It  has  a  greater  hypnotic  effect  than  has  urethane.  The 
urethanes  are  diuretics,  as  well  as  hypnotics.  In  the  body 
they  are  oxidized  to  carbon  dioxide  and  urea. 

61.  Guanidine  is  formed  when  cyanamide  reacts  with 
ammonium  chloride : 


c 


\NHS 


/NH2 

C=NH    HC1 
\NH2 

Guanidine  hydrochloride 


118     Organic  Chemistry  for  Students  of  Medicine 

It  may  be  regarded  as  urea  in  which  the  oxygen  is  re- 
placed by  the  divalent  =NH  group  (imino  group).  It 
also  results  from  heating  thiourea  through  the  loss  of 
hydrogen  sulphide : 


H2N— C  S—  N 


H2  =  NH2—  CN 


/NH2 
NH2—  C  =  N  +  NH3  •  HCNS  =  C  =NH  +  HCNS 

Cyanamide  Ammonium  thiocyanate 


Guanidine  is  a  colorless  crystalline  compound  of  a 
strongly  basic  character  which  absorbs  moisture  and 
carbon  dioxide  readily,  forming  a  solution  of  guanidine 
carbonate,  [NH  =C  =  (NH2)2]HCO3. 

It  is  hydrolyzed  by  alkalies  to  urea  and  ammonia  : 

/NH2  XNH2 

C=NH  +  H2O  =  CO(         +  NH3 
\NH2  \NH2 

Guanidine  reacts  with  strong  nitric  acid  to  form  a  nitro 
compound,  nitro  guanidine,  which  on  reduction  yields 
amino  guanidine  : 

/NH—  NO2  /NH—  NH2 

C=NH  +  6H  =  C=NH 

\NH2  \NH2 

The  latter  is  hydrolyzed  by  boiling  with  dilute  acids  or 
alkalies,  forming  hydrazine  (32),  carbon  dioxide,  and  am- 
monia. 

62.  Arginine  is  an  amino  acid  obtained  by  the  hy- 
drolysis of  proteins  by  mineral  acids.  On  hydrolysis  by 
alkalies  it  is  split  up  into  urea  and  ornithine,  an  acid  con- 


The  Fatty  Acids  119 

taining  five  carbon  atoms  and  two  amino  groups,  which 
is  known  by  its  behavior  and  synthesis  to  be  a-S-diamino 
valerianic  acid  (71).  Furthermore  arginine  is  synthesized 
by  the  condensation  of  cyanamide  and  ornithine : 

/NH2  NH2 

C  =  N+HjN— CH2— CH2— CH2— CH— COOH= 

Cyanamide  Ornithine 

^/NH2  NH2 

^NH— CH2— CH2— CH2— CH— COOH 

a-amino-6-guanidine  valerianic  acid  (Arginine) 

Its  cleavage  into  urea  and  ornithine  is  illustrated  by  the 
reaction : 

NH2   ,- 

NH2 

"NH— CH2— (CH2)2— CH— COOH 

"  H 

NH2  NH2 

I  1 

=     CO  +  NH2— CH2— (CH2)2— CH— COOH 

NH2 

On  vigorous  treatment  with  alkalies  the  urea  passes  on 
into  ammonia  and  carbon  dioxide  (57). 

Arginine  is  a  white  crystalline  compound  which  melts  at 
207.5°  with  decomposition.  It  is  easily  soluble  in  water, 
but  insoluble  in  alcohol.  It  is  precipitated  by  phospho- 
tungstic  acid,  and  by  silver  nitrate  in  the  presence  of 
barium  hydroxide. 


120     Organic  Chemistry  for  Students  of  Medicine 

63.   Aminoacetic  Acid,  glycine,  glycocoll,  /^u  _^QQTT 

is  found  in  the  free  state  in  the  adductor  muscle  of  the 
scallop  and  in  plant  juices.  It  is  a  constituent  of  many 
proteins  and  is  formed  from  these  on  hydrolysis  by  acids. 
It  is  the  only  amino  acid  derived  from  proteins  which 
is  certainly  dispensable  from  the  diet  during  growth. 
It  plays  an  important  role  in  the  body  as  a  protective 
substance,  being  condensed  with  several  types  of  organic 
acids  which  are  toxic,  forming,  with  the  separation  of 
water,  combinations  which  are  of  very  much  lower 
toxicity.  An  example  of  such  a  union  is  hippuric  acid 
(see  Hippuric  Acid).  Glycocoll  is  also  a  constituent  of 
bile,  where  it  exists  combined  with  cholic  acid  as  glyco- 
cholic  acid. 

Glycocoll  is  both  an  acid  and  base  by  reason  of  its  car- 
boxyl  and  amino  groups,  but  these  neutralize  each  other's 
effects  so  that  its  solutions  react  neutral  to  litmus,  phenol- 
phthalein,  and  certain  other  indicators.  It  forms  salts 
with  bases,  the  most  important  because  of  its  tendency  to 
crystallize  being  that  with  copper : 

NH2— CH2— COCk 

)Cu 
NH2— CH2— COCK 

This  salt  forms  a  deep  blue  solution.  It  likewise  forms 
salts  with  acids,  e.g. : 

CH2— NH2  •  HC1 
COOH 

Glycocoll  chlorhydrate 


The  Fatty  Acids  121 

These  salts  are  crystalline,  but  are  extremely  soluble  in 
water  and  are  acid  in  reaction. 

Of  great  importance  in  the  isolation  of  glycocoll,  as 
well  as  other  amino  acids,  is  the  ethyl  ester.  It  is  formed 
by  passing  dry  HC1  gas  into  a  suspension  of  the  amino  acid 
in  absolute  alcohol.  As  the  hydrochloride  is  formed,  it 
goes  into  solution  and  is  then  esterified.  When  the  alcohol 
is  evaporated  the  hydrochloride  of  the  ester  is  obtained. 
From  this,  on  treatment  with  strong  sodium  hydroxide,  the 
ester  is  set  free  from  the  HC1  and  can  be  extracted  with 
ether.  All  the  esters  of  the  amino  acids  are  soluble  in 
ether. 

Glycocoll  ester  chlorhydrate  is  very  sparingly  soluble  in 
CH2— NH2  •  HC1 


COOC2 


absolute  alcohol,  which  contains  all  the  HC1  gas  which  it 
can  dissolve  and  crystallizes  from  such  a  solution  to  an 
extent  approximating  a  quantitative  separation.  This 
principle  has  been  utilized  for  its  estimation  and  prepara- 
tion. 

Glycocoll  ester  distills  with  some  decomposition  at 
ordinary  pressures  at  150°.  Under  diminished  pressure  it 
distills  without  decomposition. 

With  HNO2  glycocoll,  like  other  amino  acids,  decom- 
poses with  the  formation  of  a  hydroxy  acid  and  elementary 
nitrogen. 

CH2— COOH+HONO  =CH2OH— COOH  +N2  +H2O 
NH2 


122    Organic  Chemistry  for  Students  of  Medicine 

With  formaldehyde  its  amino  group  condenses  to  form 
a  methylene  derivative  which  has  no  basic  properties  and 
can  be  sharply  titrated  with  alkali  and  an  indicator : 

CH2— COOH  +  HCHO  =CH2— COOH 

|  |  +H20 

NH2  N=CH2 

Amino  acids,  when  treated  with  acid  chlorides,  yield 
acetyl  derivatives  of  the  following  type : 

CH2NH2  CH2— NH— CO— CH3 

|  +  CH3— COC1  =  |  +  HC1 

COOH  COOH 

Acetyl  glycocoll 

Acetyl  derivatives  of  the  amines  and  amino  acids  are 
readily  hydrolyzed  into  acetic  acid  and  free  amino  group 
by  boiling  with  dilute  alkalies.  Derivatives  of  this  class 
can  be  formed  by  employing  chlorides  of  other  organic 
acids,  as  propionyl  or  butyryl  chlorides.  The  groups 
are  collectively  known  as  acyl  radicals,  and  the  process  of 
forming  esters  from  alcohols  and  acid  chlorides  or  amides 
from  amines  and  acid  chlorides  is  known  as  acylation. 

Acyl  derivatives  can  frequently  be  purified  much  more 
satisfactorily,  because  of  greater  insolubility  or  greater 
tendency  toward  crystallization,  than  the  alcohols  or 
amines  themselves,  and  are  useful  for  the  isolation  and 
purification  of  many  compounds,  these  being  afterward 
regenerated  by  hydrolysis : 

CH2— NH— CO— CHs  CH2— NH2 

|  +HOH  =  |  +CH3COOH 

COOH  COOH 


The  Fatty  Acids  123 

Of  special  value  in  the  isolation  and  purification  of 
various  amino  acids  are  the  compounds  analogous  to  the 
acyl  derivatives,  obtained  from  certain  aromatic  acids. 

Creatine,  methyl-guanidme  acetic  acid, 

NH2 

NH=€ 

\    /CH3 
N( 
\CH2— COOH 

is  found  in  muscle  and  organ  tissues  of  vertebrates,  but 
is  not  found  in  invertebrates.  It  is  remarkably  constant 
in  amount,  being  found  in  human  muscle  to  the  extent  of 
.39  per  cent,  and  .52  per  cent  and  .45  per  cent  respectively 
in  the  muscle  of  the  rabbit  and  cat.  It  is  not  found  in 
normal  urine,  but  appears  when  carbohydrates  are  absent 
from  the  diet.  It  is  not  known  how  creatine  is  formed 
in  the  body. 

Creatine  is  a  colorless  crystalline  compound  with  a 
bitter  taste,  which  contains  one  molecule  of  water  of  crys- 
tallization which  it  loses  at  100°.  It  is  a  base  and  forms 
salts  with  acids.  It  is  formed  synthetically  by  the  con- 
densation of  cyanamide  with  methyl-amino  acetic  acid: 

NH2 

XTTT  r*TJ  / 

i>  xi2  v-'-tia  / 

+       /  =HN= 

C  =  N     HN— CH2— COOH 

N 
\ 
CH2— COOH 


124     Organic  Chemistry  for  Students  of  Medicine 

It  is  soluble  in  74.4  parts  of  water  at  10°  ;  100  cc.  of  85 
per  cent  alcohol  at  17°  dissolve  .008  grams.  On  heating 
with  alkalies  it  is  hydrolyzed  into  urea  and  sarcosine  or 
methyl  glycocoll. 

NH2  NH2 

/  I        CH3 

HN=:C  +HOH  =  CO+  | 

\  /CH3  |         NH—  CH2—  COOH 

N  NH2  Sarcosine 

\CH2—  COOH 

Creatinine  is  the  inner  anhydride  of  creatine.  It  is 
formed  from  creatine  by  boiling  with  mineral  acids,  which 
causes  the  abstraction  of  the  elements  of  water  : 

NHs 

/NHH  / 

HN=C  —  H2O  =  HN=C 


\  /CH3  \  /CH3 

N  N  -  CH/ 

\CH2—  COOH  Creatinine 

This  compound  is  a  never  failing  constituent  of  the  urines 
of  mammals.  The  daily  excretion  for  man  is  .75  to  1.5 
gram,  and  on  diets  free  from  creatine  or  creatinine  the 
output  is  surprisingly  constant  and  is  independent  of  the 
intake  of  protein.  Its  precursor  in  the  body  is  unknown. 

Creatinine  is  soluble  in  11.5  parts  of  cold  water  and  more 
readily  in  hot.  It  dissolves  in  625  parts  of  cold  absolute 
alcohol.  It  is  a  stronger  base  than  ammonia  and  displaces 
the  latter  from  its  salts.  The  most  important  salts  are  the 
potassium  creatinine  picrate, 

C4H7ON3  -  C6H307N3  •  C6H207N2K 


The  Fatty  Acids 


125 


and  the  zinc  chloride  double  salt,  (C4H7ON3)2ZnCl2.  The 
most  important  color  reaction  of  creatinine  is  that  with 
picric  acid  and  sodium  hydrate.  The  color  closely  resem- 
bles the  deep  orange  of  a  solution  of  potassium  dichromate. 
The  Betaines.  —  These  form  a  group  of  natural 
bases.  The  simplest  member  of  the  group  is  betaine  or 
trimethyl  glycocoll  anhydride. 

CH2  — N(CH3)3  CH2— N(CH3)3 

I         -J-  ^H.0      I          I 

CQO[HOH|  co— o 

Betaine 

Trimethyl  ammonium 
Acetic  acid  (hypothetical) 

Its  relation  to  the  following  bases  is  of  interest : 


:H2—  IS 
UH2 
3H2 

:o  —  ( 

y-n-butyrc 
betaine 

I(CH3)3 
3 

» 

CH—  NH           ( 

II              >H 

c        N^        ( 

^H2  —  CH2 

i 

:n2    CH—  co 

\/     1 
/\ 

CH8    CHa 

Stachydrine  or 
Proline-betaine 

\-s                IN                       v 

CH2 

1 
CH—  N(CH3)3 

1         1 
CO—  O 

Trimethyl  histidine 

CH2— CH2OH 

I 
N=(CH3)3 

I 
OH 

Choline 


OH 

Neurine 

CH2—  CH 


/O 
< 
NO 


CH2— CO  OH 


Ns 
i 


OH 


OH 


Muscari  ae 


Betaine 


126    Organic  Chemistry  for  Students  of  Medicine 

The  betaines  are  found  in  numerous  plant  extracts. 
Those  from  mushrooms  and  spores  have  been  most 
investigated. 

y-n-butyro  betaine  has  been  isolated  from  putrid  meat ; 
trimethyl  histidine  and  muscarine  from  mushroom  extract ; 
stachydrine  from  various  plants ;  and  choline  and  neurine 
from  the  brain,  the  latter  only  after  decomposition. 

64.  Acid  Anhydrides.  —  There  exists  an  important  class 
of  compounds  which  may  be  regarded  as  derived  from  two 
molecules  of  acid  by  the  abstraction  of  a  molecule  of 
water.  These  are  known  as  acid  anhydrides : 

CH3— COOH  CHa— OX 

>0  +  H20 
CH3— COOH  CH3— COX 

Acetic  anhydride 

Corresponding  anhydrides  of  the  other  fatty  acids  are 
known.  The  lower  members  are  liquids ;  those  of  higher 
molecular  weight,  solids  of  neutral  reaction.  The  lower 
members  react  readily  with  water,  regenerating  the  acids 
from  which  they  were  formed  : 

CH3— COV 

>O  +  H2O  =  2  CH3COOH 

CH3— COX 

\ 

The  higher  members  are  much  more  stable  toward 

water.  Acid  anhydrides  react  with  alcohol  to  form  esters 
in  the  sense  of  the  following  equation : 

R— CO.          HOR' 

>O  +  =2  R— COOR'  +  H2O 

R— COX         HOR' 

Acid  anhydride  Alcohol  Ester 


The  Fatty  Acids  127 

They  are  therefore  useful  in  the  same  way  as  are  the  acyl 
chlorides  for  acylating  alcohols.  With  primary  and 
secondary  amines  they  react,  producing  acyl  derivatives  : 

CH3—  CO,  H2N—  R 

>0  +  =  2CH3—  CO—  NH—  R  +H2O 

H2N—  R 


Acetic  anhydride,  (CH3  —  CO)2=O,  is  the  most  impor- 
tant of  the  anhydrides  of  the  fatty  acids.  It  is  a  mobile 
liquid  of  suffocating  odor,  B.P.  137°,  Sp.  Gr.  1.073  at  20°. 
It  is  a  reagent  of  great  importance,  being  employed  for  the 
production  of  acyl  derivatives. 

65.  Propionic  Acid,  CH3—  CH2—  COOH,  the  next 
homologue  of  acetic  acid,  is  found  in  sweat  and  in  mixtures 
resulting  from  the  putrefaction  of  proteins  by  bacteria, 
where  it  is  derived  from  certain  amino  acids  by  reactions 
which  will  be  described  later.  It  is  formed  from  ethyl 
chloride  through  propionitrile,  as  an  intermediate  product  : 

(1)  CH3—  CH2C1  +  KCN  =  CHg—  CH2—  CN  +  KC1 

(2)  CH3—  CH2CN  +  2  H20  =  CH3—  CH2—  COOH 


It  is  likewise  formed  by  the  oxidation  of  primary  propyl 
alcohol  : 

CH3—  CH2—  CH2OH  +  3  O  =  CH3—  CH2—  COOH 

+  H20 

This  mode  of  formation  makes  clear  its  structure.  It  is 
a  liquid  with  an  odor  which  is  suggestive  of  acetic  acid,  but 
is  easily  distinguishable  from  it.  B.P.  140:7°.-  It  is 
soluble  in  water  in  all  proportions,  but  much  less  so  in 


128    Organic  Chemistry  for  Students  of  Medicine 

strong  calcium  chloride  solutions.  On  adding  this  salt 
to  its  solutions  it  separates  as  an  oil.  Propionic  acid 
is  difficult  to  test  for  with  certainty,  since  its  properties 
are  so  closely  similar  to  those  of  its  immediate  homologues, 
acetic  and  butyric  acids.  The  silver  salt  contains  59.65  % 
of  silver,  and  the  barium  salt  48.40  %  of  barium.  The 
analysis  of  these  salts,  both  of  which  are  sparingly 
soluble  in  water,  is  the  most  convincing  qualitatitive  test, 
a-chlor  propionic  acid,  CH3 — CHC1 — COOH,  is 
formed  by  the  direct  action  of  chlorine  upon  propionic 
acid  in  the  sunlight.  The  isomeric  /3-chlor  derivative, 
CH2C1— CH2— COOH,  is  likewise  formed  to  some  extent. 
The  structure  of  these  acids  is  made  clear  by  other  methods 
of  formation ;  thus  acetaldehyde  adds  hydrocyanic  acid, 
forming  hydroxy  propionitrile : 


CH3 

CH3 

CH3 

1        + 

HCN-CH      1*2. 

1 
CHOH  +  NHs 

CHO 

l\ 

1 

OH 

COOH 

CN 

a-hydroxy  propionic  acid,  or  lactic  acid,  yields  when 
treated  with  PC15  a  product  in  which  both  the  hydroxyl 
group  of  the  carboxyl  and  that  on  the  a-carbon  atom  are 
replaced  by  chlorine,  viz. :  a-chlor  propionyl  chloride, 
CH3— CHC1— COC1.  This,  like  acid  chlorides  in  general, 
is  decomposed  by  water,  forming  a-chlor  propionic  acid  : 

CH3— CH2C1— COC1  +  HOH  =  CH3— CHC1— COOH 

+  HC1 


The  Fatty  Acids  129 

a-chlor  propionic  acid  is  of  interest  because  it  can  be 
employed  either  for  conversion  into  lactic  acid  or  into 
a-amino-propionic  acid,  or  alanine,  one  of  the  amino  acids 
derived  from  proteins  on  hydrolysis : 

CH3— CHC1— COOR  +  AgOH 

=  CH3— CHOH— COOR  +  AgCl 

Lactic  acid  eater 

CHs— CHC1— COOR  +  NH3 

=  CH,— CH— COOR  +  HC1 

NH2 

Alanine  ester 

66.  Lactic  Acid,  CH3— CHOH— COOH,  is  the  acid  of 
sour  milk.  It  is  formed  from  milk  sugar  by  the  action 
of  the  lactic  acid  bacteria.  Other  sugars,  as  cane 
sugar,  can  likewise  be  used  by  this  organism  with  the 
production  of  this  acid.  If  a  liter  of  10  %  cane  sugar 
solution  be  treated  with  40  grams  of  calcium  carbonate 
and  20-30  cc.  of  sour  milk  to  supply  the  bacteria  and  the 
proteins,  salts,  etc.,  necessary  for  their  multiplication,  and 
the  mixture  kept  at  37°  for  six  to  eight  days,  with  occa- 
sional agitation,  it  will  contain  a  considerable  amount  of 
calcium  lactate.  The  solution  is  then  boiled  and  evapo- 
rated to  a  small  volume  and  cooled,  when  calcium  lactate 
will  crystallize  out.  On  treating  the  crystals  with  sulphu- 
ric acid,  calcium  sulphate  and  free  lactic  acid  are  formed. 
The  lactic  acid  can  be  extracted  from  the  mixture  by  ether, 
in  which  it  is  readily  soluble.  On  distilling  off  the  ether 
lactic  acid  remains. 

Lactic  acid  occurs  in  other  fermented  substances,  such  as 


130     Organic  Chemistry  for  Students  of  Medicine 

sauerkraut  and  ensilage,  in  both  cases  arising  through  the 
agency  of  microorganisms.  The  conditions  essential  to 
the  preservation  of  succulent  vegetables  and  green  fodders 
in  these  forms  are  close  packing  in  an  air-tight  container 
from  which  the  gases  produced  can  escape.  Rapid  fer- 
mentation and  respiration  quickly  remove  the  small 
amount  of  oxygen  from  the  container,  and  through  the 
catalytic  action  of  enzymes  in  the  plant  cells  a  part  of  the 
sugars  are  converted  into  lactic  acid.  The  acidity,  to- 
gether with  the  very  considerable  rise  in  temperature, 
causes  the  death  of  most  of  the  microorganisms,  and 
the  material  is  preserved  from  putrefaction  or  further 
fermentation. 

Lactic  acid  is  a  sirupy  liquid  which  decomposes  on  dis- 
tillation at  ordinary  atmospheric  pressure,  but  can  be 
distilled  at  about  85°  if  the  pressure  be  reduced  to  .5  mm. 
of  mercury.  Distilled  in  this  way,  it  crystallizes.  The 
crystals  are  hygroscopic.  It  is  readily  soluble  in  water, 
alcohol,  and  ether,  but  insoluble  in  chloroform,  carbon 
disulphide,  or  petroleum  ether.  It  does  not  distill  with 
steam.  Lactic  acid  is  decomposed  when  heated  with 
dilute  sulphuric  acid  into  acetaldehyde  and  formic  acid : 

CH3— CHOH— COOH  =  CH3— CHO  +  HCOOH 

According  to  certain  investigators  this  reaction  is 
catalyzed  in  the  production  of  alcohol  by  fermentation, 
the  formic  acid  being  further  decomposed  into  hydrogen 
and  carbon  dioxide,  and  the  hydrogen  serving  to  re- 
duce the  aldehyde  to  alcohol.  (See  Fermentation.)  The 
most  characteristic  salt  of  lactic  acid  is  the  zinc  salt, 


The  Fatty  Acids  131 

Zn(C3H5O3)2  3  H2O.  This  is  soluble  in  52.5  parts  of  water 
at  15°.  Lactic  acid  is  frequently  identified  by  the  analysis 
of  its  zinc  salt. 

67.  Pyruvic   Acid,    CH3— CO— COOH.    This   acid   is 
formed  when  calcium  lactate  is  oxidized  with  potassium 
permanganate  and  by  other  more  complicated  reactions: 

CH3  CH3 

I  I 

CHOH+0  =  CO        +H20    (ca=iCa) 

COOca  COOca 

Calcium  lactate         Calcium  pyruvate 

It  melts  at  14°  and  boils  at  61°  under  12  mm.  pressure. 
It  is  soluble  in  water,  alcohol,  and  ether.  Biochemical 
studies  during  recent  years  have  made  it  highly  probable 
that  pyruvic  acid  is  an  intermediary  product  of  the 
catabolism  of  carbohydrates,  fats,  and  proteins  (164, 165). 
An  enzyme  discovered  by  Neuberg  in  yeast  has  the 
property  of  decomposing  pyruvic  acid  into  acetaldehyde 
and  carbon  dioxide : 

CH3— CO— COOH  ->  CH3— CHO  +  COz 

Pyruvic  acid  can  be  reduced  to  lactic  acid.  Its  relations 
to  other  compounds  will  be  more  fully  discussed  later 
(164,  165). 

68.  Stereoisomerism  of  the  Lactic  Acids.  —  In  discuss- 
ing the  peculiar  relationship  between  the  chemical  struc- 
ture of  the  amyl  alcohols  and  the  property  of  rotating  the 
ray  of  polarized  light  (20)  it  was  pointed  out  that  optical 
activity  in  amyl  alcohol  is  associated  with  the  presence  of 


132     Organic  Chemistry  for  Students  of  Medicine 

an  asymmetric  carbon  atom,  i.e.  one  whose  four  valences  are 
bound  each  to  a  different  radical  or  group.  Lactic  acid 
possesses  a  structure  which  conforms  with  the  require- 
ments of  asymmetry,  and  we  should  therefore  expect  to 
find  two  kinds  of  lactic  acid,  having  the  same  chemical 
properties  and  the  same  physical  properties  (specific 
gravity,  boiling  point,  melting  point,  etc.)  except  in  their 
behavior  toward  polarized  light.  This  is  actually  the  case. 

There  are  two  classes  of  substances  which  show  optical 
activity.  Some,  like  quartz  and  sodium  chlorate,  produce 
rotation  only  in  the  crystallized  state.  When  they  are 
dissolved  or  fused  the  optical  property  disappears.  Others, 
like  active  amyl  alcohol,  lactic  acid,  oil  of  turpentine, 
camphor,  and  sugar,  are  optically  active  whether  in  the 
crystalline  or  in  the  liquid  state,  or  in  solution.  In  the 
former  case  the  molecules  themselves  do  not  have  an  asym- 
metric structure,  but  they  unite  to  form  crystals  which  do. 
We  may  liken  this  to  the  construction  of  a  spiral  staircase, 
an  asymmetrical  structure  from  symmetrical  bricks.  When 
the  staircase  is  again  resolved  into  its  component  bricks, 
the  asymmetry  disappears.  The  optical  activity  of  these 
substances  depends  therefore  upon  a  peculiar  arrangement 
of  the  molecules  to  form  an  asymmetric  structure.  In  the 
case  of  compounds  which  are  optically  active  in  the  liquid 
state,  the  asymmetry  resides  in  the  molecules  themselves. 

Ordinary  lactic  acid,  obtained  either  by  fermentation  of 
milk  or  by  synthesis,  is  optically  inactive.  There  is  in  the 
normal  muscle  tissue  of  all  higher  animals,  especially  after 
activity,  an  appreciable  amount  of  dextrorotatory  lactic 
acid.  The  typhus  bacillus  and  various  vibrios  ferment 


The  Fatty  Acids  133 

cane  sugar  with  the  formation  of  levorotatory  lactic  acid, 
and  when  these  are  mixed  in  equimolecular  proportions 
there  results  the  inactive  acid  identical  with  that  obtained 
by  synthesis  or  from  fermented  milk.  Dextrolactic  acid, 
from  its  presence  in  muscle,  is  called  sarcolactic  acid.  It  is 
present  in  muscle  to  the  extent  of  .3-. 5  parts  per  thousand. 
For  brevity  the  two  forms  are  written  d-  and  1-lactic  acids. 

The  reason  for  the  difference  in  optical  properties  is  best 
explained  by  the  theory  of  Van't  Hoff  and  Le  Bel,  who 
arrived  at  the  same  conclusions  simultaneously  and  inde- 
pendently in  1874.  The  reasoning  is  briefly  as  follows : 

The  four  affinities  of  the  carbon  atom  are  not  to  be  con- 
ceived of  as  lying  in  the  same  plane,  otherwise  isomers 
should  exist  in  compounds  of  the  general  type  Caabb, 
where  a  and  b  represent  atoms  or  radicals  (20).  No  such 
isomerism  has  ever  been  observed.  The  simplest  assump- 
tion that  we  can  make  with  regard  to  the  distribution  in 
space  of  the  four  atoms  or  groups  attached  to  the  carbon 
atom  is  that  the  direction  of  each  makes  equal  angles  with 
the  directions  of  the  three  others.  This  is  equivalent  to 
saying  that  the  four  atoms  or  groups  are  situated  at  the 
solid  angles  of  a  tetrahedron  in  the  center  of  which  the 
carbon  atom  itself  is  situated. 

If  the  groups  or  atoms  are  all  alike,  they  will  be  equally 
attracted  by  the  carbon  atom  and  the  tetrahedron  will  be 
regular.  If  they  are  all  different,  the  force  with  which  each 
will  be  attracted  will  probably  be  different  and  they  will 
arrange  themselves  at  different  distances  from  the  carbon 
atom;  the  tetrahedron  will  then  be  irregular,  i.e.  it  will 
have  no  plane  of  symmetry.  Any  compounds  of  the  for- 


134     Organic  Chemistry  for  Students  of  Medicine 


mula  CHa&c  can  exist  in  two  forms  called  enantiomorphs, 
which  are  alike  in  the  sense  that  an  object  is  like  its  mirror 
image,  but  they  will  not  be  superposable. 


b' 


FlQ.    11. 


A  consideration  of  Fig.  11  will  help  to  make  this  clear : 
If  we  consider  any  group  of  three  of  the  atoms  or  groups, 


COOH 


CO.OH 


FIG.  12. 


as  Hfo,  looking  toward  the  face  about  which  they  are 
arranged,  any  order  as  H6c  which  is  clockwise  in  one 
figure  will  be  counterclockwise  in  the  other.  If  they  are 


The  Fatty  Acids  135 

at  different  distances  from  the  carbon  atom,  any  continu- 
ous curve  passing  through  the  four  atoms  or  groups  in  any 
given  sequence  will  form  a  right-handed  helix  in  one  case 
and  a  left-handed  helix  in  the  other.  Such  a  structure 
would  account  for  the  observed  optical  properties  of  such 
compounds.  According  to  this  conception  the  two  active 
lactic  acids  can  be  represented  by  the  stereo-chemical 
formulae  in  Fig.  12  : 

There  is  a  great  difference 
in  the  biological  values  of  the 
d-  and  1-lactic  acids.  When 
the  mold  Penicillium  glaucum 
is  grown  upon  a  solution  of 
ammonium  lactate  prepared 
from  inactive  fermentation  COOH 

,      ,.  .,  ,  .    .  Fio.  13. 

lactic    acid,    and    containing 

suitable  inorganic  salt  additions,  it  is  found  after  a  time 
that  the  solution  is  dextrorotatory.  The  1-  form  is  used  up 
as  a  source  of  carbon  by  this  mold,  but  not  the  d-  form. 
It  has  been  already  stated  that  synthetic  lactic  acid  is 
inactive  and  consists 'of  equal  numbers  of  the  d-  and  1- 
forms.  A  brief  consideration  will  show  that  this  must 
inevitably  be  the  result.  If  in  Fig.  13  we  substitute  one 
of  the  hydrogen  atoms  of  propionic  acid,  H  or  H',  by  some 
other  element  or  radical,  we  must  by  the  law  of  chance 
substitute  H  as  frequently  as  H',  since  in  propionic  acid 
there  is  a  plane  of  symmetry  from  which  H  and  H'  are 
equidistant,  and  any  force  which  comes  into  play  in  the 
motions  of  the  symmetric  molecules  of  a  gas  or  liquid 
which  affects  one  of  these  hydrogen  atoms,  has  an  equal 


136     Organic  Chemistry  for  Students  of  Medicine 


chance  of  affecting  the  other.  In  the  synthesis  of  hydroxy 
propionitrile  the  same  reasoning  holds  good.  When 
hydrocyanic  acid  condenses  with  acetaldehyde,  Fig.  14, 
the  addition  will  take  place  as  frequently  according  to  one 
scheme  as  the  other,  and  the  acid  resulting  from  the  hydrol- 
ysis of  the  nitrile  must  be  inactive. 

The  formation  of  inactive  lactic  acid  in  fermentation  in- 
volves without  doubt  an  addition  of  H  and  OH  to  an  inter- 


CH 


-0-H 


mediary  product  of  bacterial  action  in  which  the  law  of 
chance  determines  the  positions  which  each  radical  takes. 
This  will  be  further  discussed  in  connection  with  fermenta- 
tion (164). 

The  production  of  1-lactic  acid  by  certain  organisms  or 
the  d-acid  in  the  muscle  tissues  results  from  the  cleavage  of 
lactic  acid  from  more  complex  compounds  (sugars)  which 
are  themselves  optically  active  and  on  which  the  positions 
of  the  H  and  OH  groups  are  already  determined  in  the 
molecule  of  the  mother  substance. 

Lactic  acid  is  decomposed  by  heating  with  sulphuric 
acid  into  acetaldehyde  and  formic  acid : 

CH3— CHOH— COOH  =  CHa— CHO  +  HCOOH 


The  Fatty  Acids  137 

This  decomposition  is  of  interest  because  it  shows  the 
easiest  line  of  cleavage  of  lactic  acid.  Acetaldehyde  is 
without  doubt  formed  from  lactic  acid  in  its  decomposi- 
tion by  living  tissues. 

69.  d-Alanine,  a-aminopropionic  acid, 

CHg—  CH—  COOH 

is  a   constituent   of   the   protein 
NH2 

molecule  and  is  formed  on  hydrolysis  of  the  proteins  by 
boiling  with  strong  mineral  acids.  It  is  present  in  silk  to 
the  extent  of  over  20  %.  It  is  formed,  as  are  all  the  other 
amino  acids  found  in  proteins,  by  complete  digestion  of  the 
latter  with  the  enzymes,  trypsin  from  the  pancreas  and 
erepsin  from  the  mucous  lining  of  the  intestine.  It  is 
formed  from  a-chlor  propionic  acid  on  treatment  with 
ammonia  : 

CH3—  CHC1—  COOH  +NH3  =  CHa—  CH—  COOH  +HC1 

NH2 

Also  by  the  interaction  of  acetaldehyde  with  ammonium 
cyanide  : 

HNH2  /NH2 

Cft—  CHO+  =     CH3—  CH(          -  +H2O 

HCN  \CN 

/NH2 
CHa—  CH  +  2H2O 


=  CH3—  CHNH2—  COOH+NH3 

The  reactions  of  alanine  with  chemical  reagents  are 
analogous  to  those  of  glycocoll  (63).     With  nitrous  acid  it 


138     Organic  Chemistry  for  Students  of  Medicine 

is  converted  into  lactic  acid.  Since  it  contains  an  asym- 
metric carbon  atom  (68)  it  possesses  optical  activity  and 
occurs  in  the  d-  and  1-  forms  and  in  the  d,  1-  form.  Its 
isomerism  is  that  of  enantiomorphs  and  is  analogous  to 
that  of  the  lactic  acids. 

Of  the  two  optical  isomers  only  the  d-  form  is  of  biolog- 
ical importance.  When  yeast  is  allowed  to  act  on  a  sugar 
solution  containing  d,  1-alanine,  the  d-  form  is  used  up  as  a 
source  of  energy,  leaving  the  1-  form  unchanged.  This 
method  is  employed  generally  in  preparing  the  form  of 
amino  acids  not  found  in  nature.  It  is  a  remarkable  fact 
that  in  the  life  processes  of  animals  and  plants,  with  but 
few  exceptions,  the  compounds  which  play  an  important 
role  are  optically  active,  and  but  a  single  optical  form  occurs 
in  nature.  In  no  case  can  the  optical  antipode  when 
synthesized  in  the  laboratory  be  substituted  for  the  nat- 
urally occurring  form  in  biological  processes. 

A  remarkable  transformation  of  one  optical  form  of 
alanine  into  the  other  occurs  when  d-alanine  is  treated  with 
nitrosyl  bromide,  and  the  resulting  1-a-brom  propionic 
acid  is  again  converted  into  alanine  by  treatment  with 
ammonia.  With  each  repetition  of  these  two  transform- 
ations the  alanine  is  changed  from  one  optical  form 
into  the  other.  The  following  scheme  will  make  this 
clear : 

d-alanine  •<—  NHs  •<—  d-a-brom  propionic  acid 

I  t 

NOBr  NOBr 

I  t 

1-a-brom  propionic  acid— >NH 3 -*- 1-alanine 


The  Fatty  Acids  139 

This  is  known  from  its  discoverer  as  the  "  Walden  trans- 
formation." 

Alanine  is  a  crystalline  compound,  soluble  in  4.6  parts  of 
water  at  17°.  It  is  nearly  insoluble  in  alcohol.  The  ethyl 
ester  can  be  distilled  under  diminished  pressure  without 
decomposition. 

CH2SH 

Cysteine,  a-amino-/3-thio  lactic  acid,  CH — NH2,  occurs 

COOH 

as  a  constituent  of  certain  proteins.  It  is  the  only 
derivative  of  proteins  which  yields  sulphur.  Cysteine  is 
acted  on  by  putrefactive  bacteria,  with  the  liberation  of 
hydrogen  sulphide  and  the  formation  of  serine. 

CH2S— S— CH2 

I  I 

CHNH2      CHNH2 


COOH 


COOH 

Cystine 

Cystine  forms  large  hexagonal  plates,  and  can  be  iden- 
tified by  their  characteristic  appearance  under  the  mi- 
croscope. 

Cystine  is  burned  to  carbon  dioxide,  water,  ammonia, 
and  sulphuric  acid  in  the  normal  body,  but  there  occurs 
an  anomaly  of  metabolism  in  which  this  amino  acid  is  reg- 
ularly excreted  in  the  urine —  the  condition  of  cystinuria. 

The  hydrogen  sulphide  of  the  digestive  tract  is  derived 
from  the  action  of  microorganisms  on  cystine. 


140     Organic  Chemistry  for  Students  of  Medicine 

CH2OH 

I 
Serine,  a-amino-/3-hydroxy  propionic  acid,  CH — NH2 


COOH 


is  another  amino  acid  found  among  the  products  of  the 
hydrolysis  of  the  proteins.  It  is  especially  plentiful  in 
silk.  It  is  closely  related  to  cystine,  on  the  one  hand,  and 
to  alanine,  on  the  other. 

70.  Butyric  Acid.  —  Two  acids  having  the  for- 
mula C3H7COOH  are  known.  Normal  butryic  acid, 
CH3—  CH2—  CH2—  COOH,  is  formed  from  primary 
propyl  iodide  by  the  action  of  KCN  and  subsequent 
hydrolysis  of  the  resulting  nitrile  : 

CH3—  CH2—  CH2I  +KCN  =  CH3—  CH2—  CH2—  CN  +KI 

CH3—  CH2—  CH2—  CN  +2  H20 

=  CH3—  CH2—  CH2—  COOH+NH3 

Isobutyric  acid  is  formed  in  a  similar  manner  from  sec- 
ondary propyl  iodide  and  KCN.  It  is  therefore  dimethyl 
acetic  acid  : 

CH3  CH3  CH3 

|  I  +2H20      | 

CHI  +KCN  =  CH  —  CN    -  >    CH—  COOH 


CH3  CH3  CH3 

Isobutyric  acid 

Normal  butyric  acid  is  found  in  butter,  as  the  glycerin 
ester,  to  the  extent  of  2-4  %.  Several  kinds  of  micro- 
organisms have  been  described  (e.g.  B.  butylicus)  which 


The  Fatty  Acids  141 

farment  sugars  with  the  formation  of  butyric  acid. 
All  of  these  produce  the  normal  acid.  It  is  not  produced 
in  putrefaction.  B.  hollobutyricus  can  produce  butyric 
acid  from  calcium  lactate.  The  mechanism  of  this  trans- 
formation can  be  discussed  more  satisfactorily  after  the 
properties  of  the  unsaturated  compounds  have  been 
treated  (164).  Normal  butyric  acid  is  a  colorless,  viscous 
liquid  with  a  pungent,  disagreeable,  rancid  odor.  It  is 
readily  soluble  in  water,  but  is  "  salted  out  "  by  calcium 
chloride  and  other  salts.  It  boils  at  163°. 

The  calcium  salt  (C^yO^Ca  •  H2O  is  more  soluble  in 
cold  than  in  hot  water.  This  peculiar  behavior  is  prob- 
ably to  be  explained  by  the  formation  at  low  temperatures 
of  a  compound  between  the  Ca  salt  and  water  whereby  a 
hydrate  is  produced  which  is  soluble.  This  is  unstable 
at  higher  temperatures,  so  that  on  heating  the  higher 
hydrate  disappears  and  the  salt  with  the  lower  water 
content,  being  insoluble,  separates  out. 

There  is  no  a-amino  butyric  acid  corresponding  to  glyco- 
coll  and  alanine  found  in  nature.  In  very  dilute  solutions 
(.2-1.%)  and  in  the  presence  of  suitable  salts  and  a  source 
of  nitrogen,  various  molds,  yeasts,  and  bacteria  can 
employ  butyric  acid  as  a  source  of  carbon.  It  is  toxic, 
however,  and  possesses  the  property  of  paralyzing  the  motor 
nerve  endings  without  interfering  with  the  power  of  the 
muscle  to  contract. 

CH3 

71.   Isobutyric  Acid,        V}H— COOH,    is    a  product 

CH3 
of  the  putrefaction  of  proteins,  where  it  results  from  the 


142     Organic  Chemistry  for  Students  of  Medicine 

decomposition  of  valin  or  a-amino  isovalerianic  acid  (73). 
This  isomer  of  normal  butyric  acid  is  not  formed  in 
fermentation  of  the  sugars.  Its  odor  is  similar  to  that  of 
n-butyric  acid,  but  is  not  so  offensive.  It  boils  at  154° 
and,  unlike  its  isomer,  its  calcium  salt,  is  more  soluble  in 
hot  water  than  in  cold.  No  amino  derivatives  of  iso- 
butyric  acid  occur  in  nature.  Its  physiological  and  phar- 
macological properties  closely  resemble  those  of  ?i-butyric 
acid. 

72.  Valerianic  Acid,  CH3—  (CH2)3—  COOH.  —  Four 
isomers  are  possible.  There  are  but  two  of  these  which 
are  of  biological  importance,  the  most  common  one  being 
isovalerianic  or  isovaleric,  which  is  isopropylacetic  acid  : 


3v 

CH—  CH2—  COOH 


It  occurs  in  valerian  root  and  in  other  plant  juices,  and 
among  the  putrefaction  products  of  proteins,  where  it  is 
deriv'ed  from  the  amino  acid  leucine  (75).  It  results  from 
the  oxidation  of  fermentation  amyl  alcohol.  B.  P.  175°. 
It  has  an  odor  like  that  of  old  cheese. 

Bromine  acts  on  isovaleric  acid,  forming  a-brom  iso- 
valeric acid.  M.  P.  44°,  B.  P.  150°  and  44  mm.  pressure. 

Ornithine,  a-8-diamino  valerianic  acid,  does  not  occur  in 
nature  as  such  but  is  a  cleavage  product  of  arginine  (62), 
•resulting  from  the  hydrolysis  of  the  guanidine  radical. 
Ornithine  is  the  mother  substance  of  tetramethylene 
diamine,  or  putrescine,  a  base  found  in  putrefying  protein 
mixtures. 


The  Fatty  Acids  143 

CH2—  CH2—  CH2—  CH—  COOH      - 


NH2  NH2 

Qrnithine  =  CH2-CH2—  CH2—  CH2 

I  I 

NH2  NH2 

Putrescine 

73.   Amino  Isovalerianic  Acid,  Valin, 

(CH3)2  =  CH—  CH—  COOH 
NH2 

is  one  of  the  products  resulting  from  the  hydrolysis  of 
proteins  by  acids  or  by  the  digestive  enzymes.  It  is 
therefore  of  great  biological  importance.  It  is  not  present 
in  large  amounts  in  any  protein  ;  edestin,  a  globulin  from 
the  hemp  seed,  yields  more  than  any  other  protein  yet 
examined  (5.6  %). 

It  has  been  prepared  from  sprouted  lupine  seeds,  where 
it  is  formed  by  the  digestion  of  the  proteins  of  the  seeds 
by  proteolytic  enzymes  present  in  the  germinating  seeds. 
It  has  been  produced  synthetically  by  the  action  of  am- 
monia on  a-brom  valeric  acid,  a  method  analogous  to  that 
by  which  amino  acids  in  general  are  produced  (63,  69). 
The  product  of  synthesis  is  optically  inactive,  while  that 
obtained  from  proteins  is  d-valin.  The  synthetic  amino 
acid  can  be  resolved  into  its  optical  antipodes  by  a  chemi- 
cal method  discovered  by  Pasteur.  The  principle  of  this 
method  is  as  follows  : 

The  d-  and  1-  forms  of  optically  active  acids  are  exactly 
alike  in  configuration,  being  alike  in  the  sense  of  an  object 


144    Organic  Chemistry  for  Students  of  Medicine 

and  its  mirror  image,  and  have  therefore  the  same  physical 
properties  (density,  solubility,  etc.)  except  as  respects  their 
influence  upon  polarized  light  (20).  There  are  in  many 
plants  organic  bases  of  complex  constitution  which  contain 
in  their  molecules  one  or  more  asymmetric  carbon  atoms 
and  are  therefore  capable  of  existing  in  optically  active 
forms.  As  in  the  case  of  alanine  and  valin  and  other 
amino  acids  to  be  described  later,  there  is  found  in  nature 
only  one  optical  variety,  the  other  being  incapable  of  play- 
ing any  role  in  biological  processes.  Examples  of  such 
natural  plant  bases  are  quinine,  strychnine,  nicotine,  etc. 
When  now  an  inactive  mixture  of  d-  and  1-  acids  is 
treated  in  solution  with  an  optically  active  (i.e.  asymmetri- 
cal) base,  as  strychnine,  there  are  formed  salts  of  the  acid, 
e.g.  d,  1- valin,  and  base  in  the  following  combinations : 

1-strychnine  —    —  1- valin 
1-strychnine  —    —  d- valin 

The  salt  molecules  thus  produced  are  no  longer  of  the 
same  structure  and  accordingly  show  different  physical 
properties,  as  solubility,  etc  The  form  having  the  greater 
insolubility  tends  therefore  to  crystallize  out  first  when  the 
solution  is  concentrated  by  evaporation  of  a  part  of  the 
solvent.  After  recrystallization  of  the  salt  it  is  decomposed 
by  the  addition,  of  a  stronger  alkali  to  it  in  solution,  when 
the  very  sparingly  soluble  strychnine  crystallizes  out, 
leaving  the  optically  active  acid  in  solution  as  a  metallic 
salt.  The  mother  liquor  contains  the  more  soluble  isomer. 

Mention  has  already  been  made  of  a  second  method  of 
preparing  one  optical  isomer  from  the  inactive  mixture 


The  Fatty  Acids  145 

which  is  based  upon  the  ability  of  a  living  organism  to  use 
as  food  but  one  of  the  two  forms  (66).  This  method 
applies  only  to  the  preparation  of  that  form  which  has  no 
biological  value. 

,  Valin  is  the  mother  substance  of  isobutyl  alcohol,  as  it  is 
formed  through  the  agency  of  yeast  during  fermentation. 
Yeast  possesses  the  power  to  catalyze  the  following  reac- 
tions : 

(1)  CH3 

>CH— CH— COOH 
CH/  | 

NH2 


f^TT 
3NC 


H-CH-COOH  +  NH3 
/ 


OH 

a-oxy-isovaleric  acid 

(2)  CH3 

>CH— CH— I 
CHa/ 

OH 


CH—  CH2OH  +  C02 


Isobutyl  alcohol 

It  is  this  type  of  decomposition  of  various  amino  acids 
which  leads  to  the  formation  of  fusel  oil.  Amyl  alcohol 
has  its  origin  in  a  similar  manner  from  the  amino  acid 
leucine  (75). 

Under  the  influence  of  putrefactive  bacteria  (anaerobic 
conditions)  the  amino  acids  are  deaminated,  i.e.  lose  the 


146     Organic  Chemistry  for  Students  of  Medicine 

amino  group  without  losing  the  carboxyl  group  (decar- 
boxylation). 

CH3, 

^>CH— CH— COOH  +  2  H 

NH2 

CH3y 

>CH— CH2— COOH  +  NH3 
CH/ 

Isovaleric  acid 

It  is  by  this  type  of  reaction  that  the  valeric  acid  in 
feces  and  other  putrefying  mixtures  is  formed.  The 
anaerobic  organisms  have  the  power  of  obtaining  oxygen 
from  certain  organic  compounds,  and  in  so  doing  hydrogen 
becomes  available  in  the  nascent  state,  when  it  effects  such 
reactions  as  that  just  described. 

74.  Caproic  Acid,  CH3(CH2)4— COOH.  —  The  normal 
acid  has  been  found  in  several  plants,  but  it  is  of  little 
biological  importance.  One  of  the  isocaproic  acids,  iso- 
butyl  acetic, 

(CH3)2  =  CH— CH2— CH2— COOH 

is  contained  in  butter  in  the  form  of  its  glycerol  ester. 
This  isomer  is  of  interest  because  one  of  its  derivatives, 
viz.,  a-amino-isobutyl  acetic  acid,  called  for  brevity 
leucine,  is  a  regular  constituent  of  the  proteins,  from  which 
it  results  on  hydrolysis. 

Lysine,  a-e-diamino  caproic  acid,  is  one  of  the  amino 
acids  derived  from  the  hydrolysis  of  proteins.  It  together 
with  arginine  (62)  and  histidine  were  formerly,  and  still  to 
some  extent  are,  designated  as  the  "hexone  bases"  because 


The  Fatty  Acids  147 

they  each  contain  six  carbon  atoms,  and  it  was  suspected 
that  they  played  a  special  role  in  the  formation  of  sugar 
from  proteins  in  the  body.  This  is  now  known  not  to  be 
the  case. 

Lysine  is  a  basic  amino  acid,  and  is  precipitated  along 
with  the  arginine  and  histidine  by  phosphotungstic  acid. 
The  three  are  collectively  known  as  the  diamino  acids. 
This  is  not  a  fortunate  name,  since  one  of  the  three,  histi- 
dine, contains  but  a  single  amino  group. 

Putrefactive  bacteria  act  on  lysine,  causing  an  elimina- 
tion of  carbon  dioxide  from  the  carboxyl  group,  forming 
pentamethylene  diamine,  cadaverine,  which  occurs  in 
putrefying  protein  mixtures. 

CH2— CH2— CH2— CH2— CH— COOH     -  CO2 


NH2  NH2 

Lysine 


CH2 —  CH2 — CH2 — CH2 — CH2 

NH2 

Pentamethylene  diamine 


Vv'-LJ.} 

NH2 


X 

75.  Leucine,  >CH— CH2— CH— COOH.— Many 

CH/  | 

NH2 

proteins  yield  10-20  %  of  this  amino  acid  on  hydrolysis. 
The  1-  form  only  occurs  in  nature.  The  structure  of 
leucine  is  established  by  its  synthesis  from  isoamyl 
alcohol.  This  is  oxidized  to  the  corresponding  aldehyde, 
which  is  then  condensed  with  hydrocyanic  acid  to  form 
the  a-oxynitrile  of  caproic  acid.  The  latter  reacts  with 


148    Organic  Chemistry  for  Students  of  Medicine 

ammonia  with  the  replacement  of  the  hydroxyl  by  an 
animo  group.  On  hydrolysis  of  the  nitrile  to  the  corre- 
sponding acid  inactive  leucine  results  : 

CH3v 

>CH—  CH2—  CH2OH  +O 
CH3/ 

CH3v 

CH-CH2-CHO  +HCN  +  NH, 


\ 

>CH-CH2-CH-CN         +  2  H2O—  NH3 
CH/  | 

NH2 

a-amino-isovaleronitrile 

CH3\ 

>CH—  CH2—  CH—  COOH 
CHs/  | 

NH2 

Leucine 

Leucine  is  the  mother  substance  of  the  inactive  isoamyl 
alcohol  of  fermentation.  The  reactions  by  which  it  is 
probably  formed  were  described  under  valin  (73).  It  is 
not  definitely  established  however  whether  or  not  the 
steps  in  the  reaction  involve  the  formation  of  isovaleralde- 
hyde  and  formic  acid  : 


v 

>CH—  CH2—  CHOIH—  COOH 
CH/  i 

and  the  subsequent  reduction  of  the  aldehyde  to  isoamyl 
alcohol.     Such  a  course  is  in  harmony  with  the  well-known 


The  Fatty  Acids  149 

tendency  of  lactic  acid  to  separate  into  acetaldehyde  and 
formic  acid  (66). 


v 

76.   Isoleucine,  >CH—  CH—  COOH, 

CH3  -  CH/  | 

NH2 

a-amino-methyl-ethyl  propionic  acid,  has  been  isolated  from 
beet  molasses  and  from  germinated  peas,  and  occurs 
among  the  hydrolysis  products  of  many  proteins.  Since 
so  far  as  is  known  all  of  the  amino  acids  found  in  proteins, 
with  the  single  exception  of  glycocoll,  are  indispensable 
in  the  diet,  all  amino  acids  so  derived  are  of  the  greatest 
interest  and  importance. 

Isoleucine  is,  like  leucine,  used  by  yeasts  as  a  source 
of  nitrogen  and  energy.  It  undergoes  cleavage  into  an 
optically  active  amyl  alcohol,  secondary  butyl  carbinol, 
by  the  loss  of  carbon  dioxide  and  ammonia  : 


x 

>CH—  CH—  COOH  +  H2O 
CH3—  CH 

NH2 


2OH  +  CO2  +  NH3 
0.0.3  — 


Putrefactive  organisms  change  isoleucine  into  isocaproic 
acid,  which  is  found  in  feces  (74). 

77.  Higher  Fatty  Acids.  —  From  C6  upward  only  those 
members  of  the  fatty  acid  series,  CnH2nO2,  have  any  im- 
portance which  contain  an  even  number  of  carbon  atoms. 
Those  with  an  uneven  number  of  C  atoms  either  do  not 


150     Organic  Chemistry  for  Students  of  Medicine 

occur  or  are  found  but  seldom  and  in  traces.  This  remark- 
able fact  has  led  to  much  speculation  as  to  the  mode  of 
formation  of  the  fatty  acids  in  the  plant  and  animal 
world,  since  any  proposed  series  of  chemical  changes  which 
lead  to  the  building  up  of  these  acids  in  nature  must,  to 
constitute  a  tenable  hypothesis,  produce  the  even  members 
only.  Recently  Miss  Smedley  of  England  has  carried  out 
synthetic  work  which  throws  much  light  on  the  mecha- 
nism of  this  synthesis.  Its  description  must  be  deferred 
until  certain  other  compounds  are  described  (165). 

The  interest  in  the  fatty  acids  from  C6  to  'Ci8  depends 
upon  their  great  biological  value  as  constituents  of  the  fats. 
None  of  the  fatty  acids  containing  more  than  six  C  atoms 
are  found  in  nature  in  the  form  of  their  amino  derivatives. 
By  definition  fats  are  the  esters  of  the  triatomic  alcohol 
glycerol  with  the  fatty  acids.  Accordingly  the  ester  of  acetic 
or  propionic  acids  would  be  classed  chemically  with  the 
fats,  although  they  do  not  have  the  characteristic  physical 
properties  of  the  fats,  viz.  a  smooth,  greasy  feel,  insol- 
ubility in  water,  and  oily  character  when  melted.  The 
term  fat  usually  signifies  only  those  members  of  the  series 
which  possess  the  physical  properties  of  fats.  The  names 
of  the  fats  are  (derived  from  the  name  of  the  fatty  acid 
with  the  ending  -in  substituted  for  -ic.  Thus  the  tri- 
ester  of  glycerol  with  formic  acid  is  triformin ;  with  acetic 
and  butyric  acid,  triacetin,  tributyrin,  etc. 

Since  three  esters  are  possible  according  as  one,  two,  or 
three  acid  radicals  are  joined  in  ester  formatign  with  one 
molecule  of  glycerol,  we  distinguish  mono-,  di-,  and  tri- 
butyrin, caproin,  etc. 


The  Fatty  Acids  151 

The  fatty  acids  which  are  of  biological  importance  as 
components  of  fats  are,  beginning  with  C4 : 

M.  P. 

Butyric  acid  C4H8O2  -7.9° 

Caproic  acid  C6Hi2O2  -1.5° 

Caprylic  acid  C8Hi6O2  16.0° 

Capric  acid  CioH2oO2  31.4° 

Laurie  acid  Ci2H24O2  43.6° 

Myristic  acid  Ci4H28O2  53.8° 

Palmitic  acid  Ci6H32O2  62.6° 

Stearic  acid  Ci8H36O2  69.3° 

Arachic  acid  C2oH40O2  77.0° 

Behenic  acid  C^EL^C^  85. Oc 

Lignoceric  acid  C24H48O2  80.5° 

Cerotic  acid  C 


Melissic  acid  C3oH6oO2        88.0° 

The  fatty  acids  above  C5  are  very  slightly  soluble  in 
water.  One  part  of  caprylic  acid  is  dissolved  in  400  parts 
of  boiling  water,  but  on  cooling  it  separates  almost  com- 
pletely in  the  crystalline  form.  The  higher  members  are 
practically  insoluble  in  water.  They  are  more  soluble  in 
alcohol  and  dissolve  readily  in  ether,  chloroform,  petro- 
leum, ether,  carbon  tetrachloride,  and  in  the  volatile  esters. 

The  most  commonly  occurring  of  the  higher  fatty  acids 
are  palmitic  and  stearic.  They  occur  as  esters  of  glycerol 
in  both  animals  and  plants.  Their  structure,  as  well  as 
that  of  the  lower  members  to  C6  which  occur  in  nature, 
is  shown  by  synthesis  and  by  degradation  to  be  normal. 
By  a  method  analogous  to  the  formation  of  the  ketones 


152     Organic  Chemistry  for  Students  of  Medicine 

(37)  the  higher  fatty  acids  are  convertible  into  the  lower 
members  of  the  series. 

Thus  when  barium  stearate  and  barium  acetate  are 
subjected  to  dry  distillation  in  a  vacuum,  barium  car- 
bonate and  margaryl-methyl-ketone  are  produced : 


Ci7H35|COQba+baO|OCCH3  =  Ci7H35— CO— CHs 

On  oxidation  of  the  ketones  the  carbon  chain  is  broken 
(37)  and  a  fatty  acid  containing  17  carbon  atoms,  margaric 
acid,  Ci7H35O2,  and  acetic  acids  are  formed.  By  repeating 
the  ketone  formation  and  oxidation  as  described  the  carbon 
chain  has  been  shortened  by  CH2  in  successive  steps  with 
the  formation  successively  of  palmitic,  myristic,  lauric, 
and  capric  acids  on  each  occasion  when  the  product  had 
an  even  number  of  carbon  atoms.  The  acids  up  to  capric 
have  been  synthesized  by  building  up  the  carbon  chain, 
e.g.  by  the  formation  of  the  nitrile  from  the  primary  halide 
of  nonane,  and  hydrolysis  of  the  nitrile  to  the  correspond- 
ing acid. 


CHAPTER  VII 
THE  UNSATURATED  HYDROCARBONS 

78.  Alkylenes  or  defines,  CnH2n.  — When  halogens 
react  with  the  hydrocarbons  of  the  paraffin  series  to  form 
derivatives  there  is  always  formed  one  molecule  of  halogen 
acid,  HC1  or  HBr,  for  each  atom  which  enters  the  hydro- 
carbon in  place  of  hydrogen.  This  is  characteristic  of 
substitution  reactions.  There  is,  however,  another  class  of 
hydrocarbons  which  behave  very  differently  toward 
chemical  agents.  When  halogen  comes  into  contact  with 
the  members  of  this  series  it  is  quickly  absorbed  or  added 
to  the  molecule  without  the  simultaneous  formation  of 
halogen  hydride.  Nascent  hydrogen  and  the  halogen 
acids  are  likewise  absorbed  by  these  hydrocarbons,  the 
resulting  compounds  derived  by  hydrogen  addition  being 
identical  with  the  hydrocarbons  of  the  CnH2n+2  series,  and 
those  formed  by  the  absorption  of  halogen  or  halogen 
acids  are  identical  with  derivatives  of  the  saturated  hydro- 
carbons of  the  same  composition,  produced  by  substitu- 
tion. Numerous  efforts  in  the  past  to  prepare  a  com- 
pound containing  but  one  carbon  atom  and  possessing  the 
properties  of  the  defines  have  been  unsuccessful.  It  has 
been  already  pointed  out  (2,  40)  that  the  occurrence  of 
many  reactions  of  compounds  containing  carbon  can  best 
be  explained  on  the  assumption  that  very  small  amounts  of 

153 


154    Organic  Chemistry  for  Students  of  Medicine 

the  radical  methylene  CH2  =  exist  in  dynamic  equilibrium 
with  molecules  of  different  types.  Thus  the  reactivity  of 
methane,  methyl  alcohol,  and  methyl  chloride  depends 
upon  the  fact  that  each  contains  a  relatively  small  per 
cent  of  active  methylene  particles  at  ordinary  temperatures  : 

/H  /    H 

H2=c;    :£H2c.  +  1 

\H  \    H 

/OH  /  /Cl        / 

H2=C(     ^±  H2C(  +H20  H2C(->H2C^+HC1 
\  N 


79.  Ethylene,  CH2  =  CH2.  —When  ethyl  alcohol  is  acted 
upon  by  concentrated  sulphuric  acid  or  zinc  chloride, 
powerful  dehydrating  agents,  water  is  abstracted  from  the 
molecule  and  the  simplest  of  the  olefines,  ethylene,  is 
formed.  The  same  change  is  effected  by  heating  ethyl  al- 
cohol alone  to  650°.  It  separates  into  ethylene  and  water  : 

CH2—  CH2    _H3OCH2—  CH2 
|          |         -  >\  ->CH2=CH2 

H        OH 

Ethyl  alcohol  Intermediary  Ethylene 

product 

Further  instances  of  the  formation  of  ethylene  by  dis- 
sociation are  the  following  : 

/H  at  800° 
Ethane      CHg—  CH(       -  >  CH2  =  CH2  +  H2 

\H 

CHs  —  CH  —  H      ,  rrpio    CH2=CH2 
v  at  oou 

Ethyl  ether  \O  +H2O 

CH3—  CH—  H  CH2  =  CH2 


The  Unsaturated  Hydrocarbons 


155 


/ONa  at  251° 

Sodium  ethylate     CH3— CH(  > 

\H       CH2=CH2+NaOH 

/Cl  a{  500° 

Ethyl  chloride    CH3— CH^      >  CH2  =  CH2  +  HC1 

\H 


Ethyl  bromide 


CH3— CH/ 


Br 


II 


CH2=CH2+HBr 


All  the  above  decompositions  take  place  at  the  tempera- 
tures named  and  the  products  on  cooling  do  not  recombine. 
Ethylene  can  therefore  be  obtained  quantitatively  by 
passing,  e.g.,  ethyl  chloride  or  bromide  through  a  tube 
heated  to  the  decomposition  point. 

The  assumption  is  made  that  two  carbon  atoms  in  the 
olefines  are  bound  together  by  a  double  bond.  Adhering 
to  the  theory  that  in  methane  and  its  substitution  products 
the  carbon  atom  occupies  the  central  position  in  a  molecule 
in  which  the  four  attractive  forces  are  directed  so  as  to 
make  equal  angles  with  one  another,  i.e.  as  toward  the 
four  solid  angles  of  a  tetrahedron,  the  structures  assigned 
to  ethane  and  ethylene  are  as  follows : 


FIG.  15. 


FIG.  16. 


156    Organic  Chemistry  for  Students  of  Medicine 

The  double  bond  does  not  bind  the  C  atoms  in  a  more 
stable  union  than  the  single  bond.  On  the  contrary,  as  has 
been  stated,  there  is  a  pronounced  tendency  for  the  double 
bond  to  absorb  with  avidity  atoms  or  groups  and  to  pass 
into  a  "  saturated  "  condition.  Compounds  containing 
the  double  bond,  are,  because  of  this  property,  spoken  of  as 
"  unsaturated  "  compounds.  The  unsaturated  compounds 
are  given  the  ending  ene  preceded  by  the  name  of  the  alkyl 
radical  from  which  they  are  derived.  This  high  reactivity 
of  the  olefmes  is  doubtless  due  to  the  existence  of  a  con- 
siderable amount  of  dissociated  particles  R — CH — CH — R 

along  with  the  form  represented  by  Figure  16,  for  the 
double  bond.  These  are  in  dynamic  equilibrium  with 
the  undissociated  form,  and  when  compounds  capable  of 
absorption  become  available,  the  dissociated  particles  are 
rapidly  removed  and  more  double  bonds  dissociate  until 
the  reaction  is  complete : 

CH2  =  CH2  ±£  CH2— CH2  i-^  CH2R— CH2R 

I          I 

Another  method  of  preparing  ethylene  and  its  homo- 
logues  confirms  the  hypothesis  advanced  concerning  its 
structure.  Thus  ethyl  iodide,  when  treated  with  aqueous 
KOH,  yields  ethyl  alcohol.  With  alcoholic  KOH  solution 
it  yields  ethylene : 

CH3— CH2I+KOH  =  CH3— CH2— OH+KI 

Aqueous 

CH3— CH2I+KOH  =  CH2=CH2+KI+H2O 

Alcoholic 


The  Unsaturated  Hydrocarbons  157 

When  ethylene  is  mixed  with  hydrogen  and  passed  over 
finely  divided  nickel  heated  to  300°,  addition  of  hydrogen 
atoms  takes  place  and  ethane  is  formed : 

CH2  =  CH2  +  H2  =  CH3— CH3 

In  a  similar  manner  halogen  acids  are  absorbed  by  the 
olefines  with  the  formation  of  halogen  derivatives  of  the 
paraffins : 

CH2  =  CH2  +  HI  =  CH3— CH2I 

This  reaction  takes  place  with  moderate  speed  at  about 
the  boiling  point  of  water,  but  HBr  reacts  much  more 
slowly  than  hydriodic  acid  and  HC1  does  not  react  at  all. 
This  finds  its  explanation  in  the  fact  that  the  acid  as  a 
molecule  is  not  added  by  the  olefine,  but  its  constituent 
atoms ;  HI  is  an  easily  dissociated  acid,  readily  liberating 
iodine,  in  the  presence  of  even  feeble  oxidizing  agents; 
while  HC1  is  a  very  stable  acid.  HBr  is  intermediate  in 
its  stability.  Since  the  bond  between  H  and  Cl  must  be 
broken  before  addition  can  take  place,  the  firm  union  in 
HC1  prevents  its  reaction. 

The  olefines  are  much  more  easily  oxidized  than  are  the 
saturated  compounds.  While  ethane  is  not  oxidized  by 
potassium  permanganate  or  chromic  acid,  the  olefines  are 
readily  attacked.  Dilute  permanganate  oxidizes  ethylene 
to  ethylene  glycol : 

CH2  =  CH2  +  HOH  +  O  =  CH2OH— CH2OH 

The  decolorization  of  dilute  permanganate  solution 
serves  to  detect  unsaturated  compounds  in  a  mixture  of 
hydrocarbons. 


158     Organic  Chemistry  for  Students  of  Medicine 

Halogens  combine  with  olefines  to  form  di-halogen 
compounds  :  CH2X  —  CH2X  (X  =  halogen)  .  The  order  of 
reactivity  is  Cl>Br>I.  The  interaction  between  the 
halogens  and  olefines  is  greatly  accelerated  by  light.  As 
we  have  seen  before  in  other  relations,  the  most  active 
halogen  forms  the  least  active  halogen  acid  with  respect  to 
olefines.  In  an  atmosphere  of  chlorine,  even  in  diffused 
light,  ethylene  burns  with  the  deposition  of  much  carbon. 
The  principal  reaction  is  represented  by  the  following 
equation  : 


Sulphuric  acid  absorbs  the  olefines  with  the  formation  of 
alkyl  acid  sulphate  : 

CH2  =  CH2  +H<\  CH3^CH2—  (X 

>SO2  =  >SO2 

HCK  HCK 

This  serves  as  a  method  of  separating  unsaturated  from 
saturated  hydrocarbons. 

Hypochlorous  acid,  HOC1,  is  absorbed  by  olefines. 
Ethylene  forms  ethylene  chlorhydrin  : 

CH2  P.  CH2  +  HOC1  =  CH2OH—  CH2C1 

The  olefines  with  2,  3  and  4  atoms  of  carbon  are  gases. 
The  higher  members  are  liquids  and  solids.  They  are  but 
slightly  soluble  in  water,  but  dissolve  in  alcohol,  ether, 
and  in  other  organic  solvents.  All  are  combustible 
with  a  smoky  flame,  and  mixed  with  air  or  oxygen 
they  form  dangerously  explosive  mixtures.  Ethylene  ab- 
sorbs two  atoms  of  bromine,  forming  ethylene  bromide, 
CH2Br  —  CH2Br.  Analogous  compounds  also  result  from 


The  Unsaturated  Hydrocarbons  159 

the  absorption  of  two  atoms  of  chlorine  or  of  iodine.  From 
such  compounds  alcoholic  potassium  hydroxide  abstracts 
one  molecule  of  halogen  acid,  forming  bromethylene  or 
vinyl  bromide,  chloride,  etc. 

CH2Br  CH2 

-HBr      I 

CH2Br  "  '   CHBr 

Vinyl  bromide 

80.  Propylene,  CH3— CH  =  CH2,  the  next  homologue 
of  ethylene,  is  prepared  in  a  manner  analogous  to  the 
latter,  from  propyl  alcohol,  or  propyl  iodide.  It  is  instruc- 
tive that  both  propyl  iodide  and  isopropyl  iodide  yield 
the  same  propylene  on  the  abstraction  of  HI  by  means  of 
alcoholic  KOH. 

TTT 

CH3— CH2— CH2I    >  CH3— CH  =  CH2 


CH3—  CHI—  CH3     -  >     CH3—  CH  =  CH2 

This  shows  that  the  iodine  and  hydrogen  which  are 
abstracted  occupied  positions  on  neighboring  carbon 
atoms.  Otherwise  the  normal  iodide  would  yield  a  ring 
structure  : 


CH2I—  CH2—  CH3    ~" 

CH2  —  CH2 

and  should  show  different  properties.  When  propylene 
adds  on  halogen  acid  the  halogen  takes  its  place  on  that 
carbon  atom  which  holds  the  smallest  number  of  hydrogen 
atoms,  i.e.  with  the  formation  of  isopropyl  iodide  : 

CH3—  CH  =  CH2  +  HI  =  CH3—  CHI—  CH3 


160     Organic  Chemistry  for  Students  of  Medicine 

81.  Propylidene  Compounds.  —  It  has  already  been 
pointed  out  (36)  that  the  chlorides  of  phosphorus  react 
with  aldehydes  and  ketones  with  the  replacement  of 

I 

the  oxygen  of  the  carbonyl  group  CO  by  two  chlorine 


atoms  C  =  C^.     Thus  propyl  aldehyde  yields  propylidene 

chloride: 

CH3-CH2—  CHC12 

and  acetone  yields  dichloracetone  : 

CH3—  CC12—  CH3 

On  removing  one  molecule  of  haloid  acid  from  compounds 
of  these  types  there  result  two  isomeric  chlor  propylenes, 
having  chlorine  linked  to  a  doubly  linked  carbon  atom. 

_  TT/"<] 

CH3—  CH2—  CHC12     -  >  CH3—  CH=CHC1 

Propylidene  chloride  a-chlor  propylene 


CH3—  CC12—  CH3    -  >    CH3—  CCUCH2 

Chloracetone  j3-chlor  propylene 

This  type  of  halogen  compound  differs  markedly  from 
the  alkyl  halides  in  which  the  halogen  is  linked  to  a  carbon 
atom  having  only  single  bonds.  While  in  the  alkyl  halides 
the  halogen  is  readily  replaceable  by  hydroxyl,  alkyl, 
amino  groups,  etc.,  this  property  is  almost  wholly  wanting 
in  compounds  whose  halogen  is  linked  to  carbon  with  a 
double  bond.  They  do  not  react  with  alkalies  to  produce 
alcohols  nor  with  sodium  ethylate  to  produce  ethers. 
Instead  there  are  formed  compounds  which  are  substitu- 


The  Unsaturated  Hydrocarbons  161 

tion  products  of  the  triple  bond  hydrocarbons,  the  acety- 
lenes (83).  From  CH3—  CC12—  CH3  by  the  abstraction 
of  two  HC1  there  never  results  a  diolefine  CH2  =  C  =  CH2, 
as  might  be  expected. 

An  isomer  of  a-  and  /9-chlor  propylene  is  known  as 
allyl  chloride,  CH2  =  CH—  CH2C1.  This  reacts  just  as 
do  alkyl  halides,  notwithstanding  the  presence  of  the 
double  bond  in  the  molecule.  Thus  with  KOH  it  yields 
allyl  alcohol  : 

CH2  =  CH—  CH2C1  +  KOH  =  CH2  =  CH—  CH2OH  +  KC1 

This  alcohol  will  be  described  later  (85). 

82.  The  Diolefines.  —  Compounds  containing  two  double 
bonds  are  known  which  have  considerable  importance. 
Allene,  CH2  =  C  =  CH2,  is  a  gaseous  hydrocarbon  which 
can  be  prepared  from  tribrom  propane  by  the  abstrac- 
tion of  one  molecule  of  HBr  by  means  of  alcoholic  KOH, 
and  the  subsequent  removal  of  the  remaining  two  bro- 
mine atoms  by  zinc  dust  : 

—HBr 
CH2Br—  CHBr—  CH2Br  -  >  CH2  =  CBr—  CH2Br 

Dibrom  propylene 

—  2Br 

-  >  CH2  =  C  =  CH2 

It  is  a  colorless  gas. 


3x 
Isoprene,          >C—  CH  =  CH2,  is  a  liquid,  B.  P.  37°. 

CH/ 

It  is  formed  by  the  destructive  distillation  of   India 
rubber,  and  also  by  passing  turpentine  through  a  tube 

M 


162     Organic  Chemistry  for  Students  of  Medicine 

heated  to  redness.     On  treatment  with  acids  it  poly- 
merizes, forming  rubber  again. 

It  is  also  formed  from  isobutyl  carbinol,  one  of  the  amyl 
alcohols,  by  the  following  series  of  transformations  : 


)CH—  CH2—  CH2OH  --  >         )CH—  CH2—  CH2C1 
CH3/  CH3/ 

+2  Cl     CH3\ 

—  >  ;CC1—  CH2—  CH2C1 

CH/ 

v 
—2  HC1  C—  CH  =  CH2 


In  the  presence  of  metallic  sodium  it  polymerizes  to  a 
product  having  the  physical  properties  of  rubber,  but  not 
identical  with  it  chemically. 

Butylenes.  —  Three  butylenes  are  known,  and  this 
number  only  is  theoretically  possible. 

CH3v 

CH3—  CH2—  CH  =  CH2  )C  =  CH2 

CH/ 

CH3—  CH  =  CH—  CH3 

They  are  prepared  by  methods  analogous  to  propylene. 
They  differ  from  ethylene  in  their  tendency  to  polymerize 
when  treated  with  H2S04  or  ZnCl2.  Numerous  higher 
homologues  of  this  series  are  known. 

83.  Acetylenes.  —  On  treatment  of  dibrom  ethane  with 
alcoholic  KOH  two  molecules  of  HBr  are  abstracted  with 


The  Unsaturated  Hydrocarbons 


163 


the   formation  of  a  still  more  highly  unsaturated  com- 
pound acetylene  :  • 

CH2Br  CHBr  CH 

-HBr    I  -HBr 


CH2Br  CH,  CH 

Dibrom  ethane  Vinyl  bromide  Acetylene 

Acetylene  is  a  gas  which  shows  all  the  properties  of  the 
olefines,  but  is  more  unsaturated  and  reacts  with  two  mole- 
cules of  halogen  acid,  four  halogen 
atoms,  etc.  In  conformity  with  the 
theory  of  the  tetrahedral  structure 
of  the  methane  molecule  the  struc- 
ture of  the  triple  bond  hydrocarbons 
is  to  be  represented  as  in  Figure  17. 
The  carbon  atoms  united  by  a 
double  bond  possess  less  freedom  of 
movement  with  respect  to  each 
other  than  those  united  by  a  single 
bond,  and  two  united  by  a  triple 
bond  possess  still  less  freedom  of 
movement  with  respect  to  each 
other.  This  conception  is  in  har- 
mony with  a  special  type  of  isomerism  which  is  shown  by 
compounds  having  the  double  bond  as  contrasted  with 
those  in  which  no  double  bond  is  present.  That  carbon 
atoms  which  are  doubly  and  triply  bound  are  under  a 
strain,  which  leads  to  their  tendency  to  change  from  the 
unstable  state  into  other  forms  is  further  indicated  by 
the  heats  of  formation  and  of  combustion  of  ethane, 
ethylene,  and  acetylene  : 


164     Organic  Chemistry  for  Students  of  Medicine 


HEAT  OF 
COMBUSTION 

HEAT  OF 
FORMATION 

Ethane            

372  3  Cal 

23  3  Cal 

Ethylene 

341  1  Cal 

-14  6  Cal 

Acetylene        

313  8  Cal 

-51  5  Cal 

Whereas  ethane  is  formed  from  its  elements  with  the 
liberation  of  23.3  Cal.  of  heat  for  each  gram  molecule, 
energy  must  be  supplied  to  induce  the  formation  of  the 
double  bond  and  still  more  to  form  the  triple  bond.  We 
may  liken  the  formation  of  these  unsaturated  compounds 
to  the  bending  of  a  bow  into  a  position  of  tension.  While 
under  a  strain  and  possessing  stored  up  energy  it  has  a 
strong  tendency  to  change  to  a  body  of  a  new  conforma- 
tion. 

When  placed  under  pressure  greater  than  two  atmos- 
pheres, acetylene  is  readily  exploded  by  a  shock.  The 
change  which  takes  place  is  one  of  polymerization,  three 
molecules  uniting  to  form  one  molecule  of  benzene.  The 
nature  of  this  change  will  be  treated  later  (166). 

Preparation. — Acetylene  is  formed  from  ethylene  bro- 
mide by  the  abstraction  of  two  molecules  of  HBr.  This  is 
readily  effected  by  heating  with  alcoholic  KOH : 

CH2Br  CH 

+2  KOH    =    III     +2KBr+2H20 
CH2Br  CH 

Metallic  zinc  abstracts  bromine  from  tetrabrom  ethane 
in  alcoholic  solution,  with  the  formation  of  acetylene : 


The  Unsaturated  Hydrocarbons  165 

CHBr2  CH 

+2Zn    =   HI    +2ZnBr2 
CHBr2  CH 

A  characteristic  property  of  hydrocarbons  containing  the 
group  HC=  is  the  formation  of  insoluble  metallic  com- 
pounds of  the  composition  C2Ag2  and  C2Cu2,  silver  and 
cuprous  acetylides  respectively,  when  acetylene  or  its 
monoalkyl  derivatives  are  passed  into  an  ammoniacal  solu- 
tion of  silver  nitrate  or  of  cuprous  chloride.  This  prop- 
erty is  utilized  in  analytical  work  to  determine  the  acety- 
lene content  of  a  mixture.  The  quantitative  capacity  to 
absorb  bromine  serves  as  an  estimation  of  the  total  un- 
saturated  group  (defines  and  acetylenes),  and  the  amount 
of  metallic  derivative  forms  a  basis  for  the  calculation  of 
the  content  of  doubly  and  triply  unsaturated  hydrocar- 
bons in  the  mixture.  These  compounds  are  highly  explo- 
sive when  dry.  They  are  decomposed  by  hydrochloric 
acid  with  the  regeneration  of  acetylene  : 

C2Ag2  +  2  HC1  =  CH  ^CH  +  2  AgCl 

Derivatives  of  acetylene  in  which  both  hydrogen  atoms 
are  substituted  by  alkyl  groups  do  not  form  these  metallic 
compounds.  Acetylene  is  most  conveniently  prepared 
by  treating  calcium  carbide  with  water.  When  lime  and 
carbon  (coal)  are  heated  together  in  an  electric  furnace,  the 
calcium  oxide  is  reduced  and  calcium  and  carbon  combine 
to  form  calcium  acetylide,  commonly  called  calcium 
carbide,  C2Ca.  This  compound  reacts  with  water  some- 
what violently  with  the  evolution  of  considerable  heat 
and  the  formation  of  acetylene  : 

C2Ca+2H2O  =  CH=CH+Ca(OH)2 


166     Organic  Chemistry  for  Students  of  Medicine 

When  liberated  through  a  suitable  burner,  acetylene 
burns  with  an  intensely  luminous  flame.  Its  mixtures 
with  air  are  much  more  dangerously  explosive  than  are 
mixtures  of  air  and  coal  gas,  due  to  the  reactive  properties 
of  the  acetylene  as  compared  with  the  paraffin  hydro- 
carbons, and  also  to  the  wide  limits  of  composition  of  air 
and  acetylene  which  form  explosive  mixtures.  Mixtures 
containing  3  to  82  per  cent  of  acetylene  are  explosive, 
while  the  limits  for  coal  gas  are  only  5  to  28  per  cent.  In 
addition  the  velocity  of  propagation  of  the  reaction  be- 
tween oxygen  (of  the  air)  and  acetylene  is  much  greater 
in  the  case  of  the  acetylene  mixture,  which  intensifies  the 
force  of  explosion. 

The  carbides  of  certain  other  metals  yield  hydrocarbons 
other  than  acetylene.  Aluminum  carbide  yields  methane 
on  decomposition  by  water.  Uranium  carbide  yields  mix- 
tures of  methane  and  of  liquid  and  solid  hydrocarbons. 

Acetylene,  CH=CH,  is  a  gas  of  unpleasant  odor.  One 
volume  of  water  dissolves  about  1  volume  of  the  gas; 
benzene  and  alcohol  dissolve  4  and  6  volumes  respec- 
tively, at  ordinary  temperatures ;  while  acetone,  which  is 
the  best  solvent,  dissolves  25  volumes,  and  much  greater 
quantities  under  pressure. 

It  can  be  synthesized  from  its  elements  by  passing  an 
electric  spark  between  carbon  poles  in  an  atmosphere  of 
hydrogen,  a  small  amount  of  methane  and  ethane  being 
simultaneously  produced.  It  is  produced  in  small  amount 
when  many  organic  substances  are  subjected  to  incom- 
plete combustion. 

Acetylene  is  more  poisonous  than  ethane  or  ethylene.     A 


The  Unsaturated  Hydrocarbons  167 

content  of  one  volume  of  the  gas  in  air  produces  narcosis 
with  failure  of  the  heart  and  of  respiration.  Higher 
homologues  of  acetylene  in  which  the  hydrogen  atoms  are 
replaced  by  alkyl  groups  are  likewise  known. 

SUBSTITUTION  PRODUCTS  OF   THE   UNSATURATED 
HYDROCARBONS 

84.  Vinyl    Alcohol,     CH2=CHOH,    has    never    been 
isolated    and    its    existence    is    uncertain.     When    vinyl 
bromide  is  treated  with  KOH  we  should  expect  the  forma- 
tion of  an  alcohol  of  this  type,  but  a  rearrangement  of 
atoms  takes  place  with  the  disappearance  of  the  double 
bond  between  the  carbon  atoms.    When  vinyl  alcohol  is 
to  be  expected,  aldehyde  is  obtained : 

CH2  =  CHBr  +  KOH  =CH2=CHOH 

^CH3— CHO+KBr 

Unstable 

In  a  similar  manner  the  abstraction  of  water  from  glycol 
leads  to  the  formation  of  acetaldehyde  and  not  vinyl 
alcohol:  CH2OH__HQ  CH2  CH3 

CH2OH~         >CHOH  CHO 

Unstable 

85.  Allyl   Alcohol,   CH2=CH— CH2OH,   is   best   pre- 
pared from  the  monoformic  ester  of   glycerol  or  mono- 
formin  : 

CH2OOCH  CH2 


C 


HOH 


CH2OH  CH2OH 


168    Organic  Chemistry  for  Students  of  Medicine 

The  structure  of  this  compound  is  made  clear  by  the 
following  behavior :  , 

(1)  It  behaves  like  an  alcohol  in  reacting  with  sodium 
with  the  evolution  of  hydrogen. 

(2)  It  yields  an  acetyl  derivative  when  treated  with  acetyl 
chloride. 

(3)  With  nascent  hydrogen  (Zn  +  H2SO4)  it  is  converted 
into  normal  propyl  alcohol.     This  shows  that  the  alcohol 
radical  is  attached  to  an  end  carbon  atom  and  is  therefore 
a  primary  alcohol. 

(4)  The  evidence  that  it  is  a  primary  alcohol  is  sup- 
ported by  the  fact  that  it  yields  an  aldehyde  and  an  acid 
containing  the  same  number  of  carbon  atoms  as  the  alcohol 
itself. 

Acrylic  Aldehyde,  Acrolein,  CH2=CH— CHO,  is  best 
prepared  by  the  abstraction  of  two  molecules  of  water  from 
glycerol.  This  is  best  effected  by  heating  with  potassium 
bisulphate.  The  reaction  which  takes  place  is  probably 
the  following : 

CH2OH  CH2  CH2 

I            -2H,o'l  " 

CHOH      z  n*u  f,  >   CH 

!  II  1 

CH2OH  CHOH  CHO 

Glycerol  Unstable  Acrolein 

This  behavior  is  in  agreement  with  experience  which,  as 
pointed  out  above,  leads  to  rearrangement  of  the  atoms 
with  the  formation  of  an  aldehyde  whenever  we  should 
expect  the  formation  of  an  alcohol  group  in  union  with  a 
doubly  linked  carbon  atom  (84). 


The  Unsaturated  Hydrocarbons  169 

Allyl  alcohol  is  found  as  an  ester  in  the  form  of  allyl 
iso-thio-cyanate,  CsHsNCS,  in  the  seeds  of  mustard.  It 
is  not  free  but  combined  with  glucose  as  aglucoside  (161). 

Allyl  Sulphide,  (C3H5)2S,  is  the  principal  constituent  of 
oil  of  garlic. 

Acrylic  aldehyde,  or  acrolein,  can  in  turn  be  oxidized  to 
the  corresponding  acid,  acrylic  acid : 

CH2  =  CH— CHO+O  =  CH2  =CH— COOH 

Acrylic  acid 

p-Amino  Acids,  R— CH— CH2— COOH,  are  unstable 

NH2 

and  readily  split  off  ammonia  with  the  formation  of  un- 
saturated  compounds.  Thus  /3-iodopropionic  acid  yields 
with  ammonia  /3-aminopropionic  acid  which  splits  off 
ammonia,  forming  acrylic  acid. 

86.  Acids  of  the  Oleic  Series,  CnH2n_2O2.  —  The  first 
member  of  this  series  of  acids,  which  differ  from  the 
saturated  fatty  acids  by  having  one  double  bond,  is  acrylic 
acid.  The  second  member,  methyl  acrylic  acid,  is  known  as 
crotonic  acid.  It  is  formed  by  the  action  of  dehydrating 
agents  upon  /3-oxy-butyric  acid.  The  latter  compound 
is  formed  directly  by  the  condensation  of  two  molecules  of 
acetaldehyde  by  the  "  aldol  condensation  "  (32,  124)  : 
CH3— CHOH— CH2— COOH 


-H2O 


CH3— CH  =  CH— COOH. 


This  acid  occurs  in  croton  oil.  It  is  a  crystalline  sub- 
stance which  melts  at  72°  and  boils  at  180°.  At  19°  it  is 
soluble  in  12.5  parts  of  water. 


170     Organic  Chemistry  for  Students  of  Medicine 

There  is  however  an  isocrotonic  acid  which  is  an  oil 
which  boils  at  172°  and  when  maintained  for  a  time  at  a 
temperature  of  170-180  goes  over  into  crotonic  acid. 
Both  of  these  acids  yield  normal  butyric  acid  on  treatment 
with  nascent  hydrogen  and  have,  therefore,  the  normal 
carbon  chain.  They  exhibit  a  kind  of  isomerism  which 
cannot  be  explained  by  the  ordinary  constitutional  for- 
mulae. This  type  of  isomerism,  which  is  peculiar  to  the 


H 


ethylene  compounds,  is  the  necessary  result  of  the  restric- 
tion of  motion  of  two  carbon  atoms  linked  by  a  double 
bond.  Thus  butyric  acid  may  be  represented  as  in  Figure 
18. 

The  system  of  the  carbon  atom  at  the  center  of  the  upper 
tetrahedron  and  its  three  combined  atoms  or  groups  should 
have  no  restriction  as  to  the  relative  positions  which  they 
may  assume  with  respect  to  the  carbon  atom  at  the  center 
of  the  lower  tetrahedron  and  its  system  of  atoms  and 
groups.  Each  should  be  free  to  rotate  freely  about 
their  common  axis,  and  all  the  possible  arrangements 
probably  occur;  and  because  all  are  constantly  shifting, 


The  Unsaturated  Hydrocarbons 


171 


one  into  every  other  possible  position,  there  is  but  one 
normal  butyric  acid. 

When,  as  in  crotonic  acid,  we  establish  the  double  bond 
(Fig.  19),  the  two  carbon  atoms  affected  by  the  double 
bond  lose  their  freedom  of  rotating  about  a  common 
axis  independently  of  each  other,  and  we  should  expect 
different  physical  properties  to  result  from  these  two  differ- 
ent structures.  This  type  of  isomerism  will  be  more 


COOH 
H' 

Cis  form  Trans  form 

FIG.  19.  —  CROTONIC  ACIDS. 


COOH 


fully  dealt  with  in  connection  with  maleic  and  fumaric 
acids  (133).  Since  a  considerable  number  of  compounds 
of  this  class  have  been  studied,  in  many  of  which  it  is  easier 
to  decide  which  compound  represents  the  cis  and  which  the 
trans  form,  the  following  generalizations  may  be  made : 
The  acid  having  the  cis  form  is  much  the  more  soluble; 
it  hag  also  the  lower  melting  point,  and  in  the  case  of  the 
monobasic  acids  is  the  stronger  acid  of  the  two  (more 
highly  dissociated). 

In  addition  to  the  two  isomers  of  crotonic  acid  just  de- 
scribed, two  other  acids  of  the  same  formula  are  known, 


172    Organic  Chemistry  for  Students  of  Medicine 

one  differing  from  crotonic  acid  in  the  position  of  the 
double  bond,  the  other  having  a  branched  structure  : 

CH2 
CH2  =  CH—  CH2—  COOH  C—  COOH 


87.  Oleic  Acid,  CigHsA,  is  widely  distributed  in  both  the 
animal  and  vegetable  fats  in  the  form  of  its  glycerol  ester, 
triolein.  It  differs  from  stearic  acid  in  having  two  less  hydro- 
gen atoms  and  in  containing  a  double  bond.  Its  carbon 
chain  has  the  normal  structure,  as  is  shown  by  its  conver- 
sion into  stearic  acid  by  the  absorption  of  two  hydrogen 
atoms  in  the  presence  of  catalyzers.  Oleic  acid  differs 
widely  from  the  saturated  stearic  acid.  It  melts  at  14° 
and  is  therefore  an  oil  at  ordinary  temperatures.  In  the 
hydrocarbons  and  acids  of  the  fatty  series  the  properties 
of  the  homologues  change  progressively  with  increasing 
carbon  content.  The  longer  the  carbon  chain,  the  higher 
the  boiling  point  or  melting  point.  In  the  unsaturated 
compounds  the  properties  tend  to  run  counterwise  to  this 
rule,  e.g.  butyric  acid  melts  at  -2°,  crotonic  acid  melts  at 
72°,  stearic  acid  melts  at  68°,  while  oleic  acid  melts  at  14°. 
It  is  colorless  when  pure  and  has  no  odor.  It  undergoes 
transformation  into  its  isomer,  elaidic  acid,  when  treated 
with  nitrous  oxide. 

Elaidic  acid  has  the  same  percentage  composition  with 
respect  to  its  elements,  the  same  molecular  weight,  and 
absorbs  the  same  amount  of  iodine  as  does  oleic  acid  (2 
atoms),  showing  that  it  still  contains  the  double  bond. 
While  oleic  melts  at  14°,  elaidic  acid  melts  at  45-47°.  This 
change  involves  the  transformation  of  the  same  type  as 


The  Unsaturated  Hydrocarbons  173 

that  represented  by  crotonic  and  isocrotonic  acid.    Oleic 
acid  represents  the  cis  and  elaidic  acid  the  trans  form. 

The  position  of  the  double  bond  in  oleic  acid  is  established 
by  the  fact  that  when  compounds  containing  this  linkage 
are  oxidized,  the  oxidation  takes  place  at  the  point  of 
unsaturation ;  thus : 

CH3— CH  =  !CH— COOH 

Crotonic  acid 

-tl^    CH3— COOH +HOOC— COOH 

Acetic  acid  Oxalic  acid 

+  4O 
CH2=CH— COOH    >    HCOOH+HOOC— COOH 

Acrylic  acid  Formic  acid 

the  oxidation  in  all  such  cases  leads  first  to  the  forma- 
tion of  two  secondary  alcohol  groups : 

CH3— CH— CH— COOH 

I         I 
OH    OH 

then  a  separation  of  the  carbon  chain.  Thus  oleic  acid 
when  oxidized  with  a  dilute  solution  of  potassium  per- 
manganate yields,  first  dihydroxy  stearic  acid,  then 
pelargonic  acid,  CHa — (CH2)7 — COOH,  and  azeliac  acid, 
COOH— (CH2)  7— COOH.  From  this  evidence  it  is  con- 
cluded that  the  double  bond  in  oleic  acid  is  at  the  middle 
of  the  chain,  i.e.  between  the  ninth  and  tenth  carbon  atoms. 
88.  Acids  with  two  Double  Bonds,  CnH2n_4O2 ;  Linolic 
Acid,  Ci8H3202.  —  In  many  plant  oils  there  occur  fatty 
acids  which  tend  to  take  up  oxygen  and  harden  to  a  resin- 
like  state.  Such  acids  show  a  chemical  behavior  which 
indicates  that  they  possess  two  double  bonds.  These  are 


174     Organic  Chemistry  for  Students  of  Medicine 

called  linolic  acid,  because  of  their  prevalence  in  linseed 
oil.  Fats  containing  this  class  of  acids  are  found  espe- 
cially in  cottonseed,  walnut,  cedar,  and  hemp  oils  and  to 
some  extent  in  corn  oil  and  in  many  other  oils,  but  not  in 
so  high  a  per  cent  of  the  whole  as  in  linseed  oil.  On  this 
property  depends  the  peculiar  value  of  the  latter  oil  for 
the  manufacture  of  paints. 

Linolic  acid  still  remains  an  oil  at  -18°.  It  absorbs  4 
atoms  of  bromine,  or  two  molecules  of  hydriodic  acid.  On 
oxidation  it  yields  a  tetrahydroxy  derivative.  On  vigor- 
ous reduction  with  hydriodic  acid  and  phosphorus,  it 
yields  stearic  acid.  Like  oleic  and  stearic  acids,  linolic 
acid  has  the  normal  and  not  a  branched  structure.  The 
tetrabromide  of  linolic  acid  is  soluble  in  all  the  ordinary  fat 
solvents  except  petroleum  ether.  This  last  solvent  dis- 
solves readily  dibrom  stearic  acid,  and  can  be  employed 
as  a  useful  means  of  distinguishing  between  the  two. 

Acids  with  three  Double  Bonds,  C»H2n-6O2;  Linoleic 
Acid,  Ci8H30O2.  —  This  acid  occurs  especially  in  linseed 
oil  and  shows  in  still  higher  degree  the  "  drying  "  property. 
It  forms  a  hexabromid,  and  when  oxidized  with  dilute 
permanganate  solution  a  hexahydroxy  stearic  acid.  The 
oils  from  many  fishes  contain  fatty  acids  containing  two 
and  three  double  bonds. 

It  is  interesting  to  note  that  the  solubility  of  the  hy- 
droxy  stearic  acids  in  water  rapidly  increases  with  increas- 
ing number  of  hydroxy  groups.  Dihydroxy  stearic  acid 
is  nearly  insoluble;  tetrahydroxy  stearic  acid,  difficultly 
soluble;  while  the  solubility  of  the  hexahydroxy  acid  is 
quite  marked. 


CHAPTER   VIII 
THE  FATS,  WAXES,   AND   RELATED  COMPOUNDS 

89.  The  Animal  Fats.  —  Most  important  among  the 
animal  fats  are  the  body  fats  of  the  ox,  sheep,  and  swine, 
and  butter  fat.  As  has  already  been  stated,  fats  are  the 
glycerol  esters  of  the  higher  fatty  acids.  The  body  fats  of 
animals  react  practically  neutral,  and  contain  but  a  trace 
of  volatile  fatty  acids.  The  relative  amounts  of  the  differ- 
ent acids  contained  in  the  fats  of  different  species  differs 
widely  and  even  the  fats  from  the  same  species  vary  in 
composition  with  the  character  of  the  food  fats.  Thus 
lard,  which  is  the  collective  term  for  the  fat  of  the  hog, 
may  melt  as  low  as  28°  when  the  diet  consists  of  corn  meal 
only,  when  it  contains  over  90  per  cent  of  olein ;  or  as  high 
as  35.6°  when  the  animals  are  fed  a  ration  of  oats,  peas, 
and  barley. 

From  the  same  animal  the  body  fats  from  different  parts 
may  show  different  melting  points  owing  to  their  variable 
content  of  olein.  Thus  the  fats  surrounding  the  kidney 
may  melt  as  high  as  43°  in  the  hog.  Triolein  is  a  liquid 
at  0°,  while  tripalmatin  and  tristearin  melt  at  62  and  71.5° 
respectively.  Human  fat  is  especially  rich  in  olein,  fre- 
quently melting  as  low  as  17.5°,  while  tallow  regularly 
melts  at  45-46°  and  the  fat  of  the  sheep  at  46-51°.  The 

175 


176    Organic  Chemistry  for  Students  of  Medicine 

relative  proportions  of  the  different  fats  in  the  mixture 
determine  the  melting  point. 

Butter  fat  occupies  a  peculiar  place  among  the  animal 
fats.  It  consists  mainly  of  a  mixture  of  palmitin,  stearin, 
and  olein,  but  contains  from  6  to  8  per  cent  of  fatty  acids 
volatile  with  steam,  as  glycerides,  i.e.,  butyric,  caproic, 
caprylic,  and  capric,  and  also  some  lauric  and  myristic 
acids.  No  other  fats  from  either  animal  or  vegetable  oils 
yield  on  saponification  so  high  a  proportion  of  volatile 
fatty  acids. 

90.  Vegetable  Fats.  —  Even  greater  diversity  of  char- 
acter is  found  among  the  vegetable  fats  than  among  those 
from  animals.  Palm  oil  consists  mainly  of  palmitin  and 
olein,  but  contains  small  amounts  of  other  glycerides. 
Cocoa  butter  contains  about  40  %  of  stearin,  20  %  of 
palmatin,  30  %  of  olein,  and  6  %  of  linolein,  together 
with  some  other  fats. 

There  is  a  class  of  fats  which  are  liquids  and  are  there- 
fore called  oils,  which  are  known  as  the  non-drying  oils  to 
differentiate  them  from  certain  others  which  have  different 
properties.  The  non-drying  oils  include  olive  oil,  the  oil 
of  wheat,  date,  hazelnut,  and  rice.  They  consist  mainly 
of  triolein. 

The  drying  oils  are  easily  oxidized  in  the  air  and  light, 
especially  after  being  heated  for  a  time  with  manganese  di- 
oxide, or  lead  oxide,  which  act  as  catalyzers  of  the  oxida- 
tion process.  This  class  includes  linseed,  cedar-nut,  hemp, 
walnut,  and  sunflower  oils,  and  a  few  others.  They  consist 
principally  of  triglycerides  of  linolic  and  linoleic  acids. 

The  semi-drying  oils  consist  principally  of  glycerides  of 


The  Fats,  Waxes,  and  Related  Compounds    177 

oleic  and  linolic  acids.  In  this  group  are  corn  and  cotton- 
seed oil  and  sesame  oil.  These  on  exposure  to  oxygen 
(air)  are  only  very  slowly  and  incompletely  converted  into 
resinous  products. 

Croton  oil  deserves  special  mention  because  of  its  marked 
pharmacological  action.  It  is  pressed  from  the  seeds  of 
Croton  tiglium,  and  is  a  sherry-colored  viscid  liquid  with  an 
acrid  taste  and  somewhat  rancid  smell,  and  a  fluorescent 
appearance.  It  is  a  violent  purgative,  in  most  cases  a 
single  drop  being  sufficient  to  effect  intestinal  activity. 
When  rubbed  upon  the  skin  it  produces  rubefaction  and 
pustular  eruption. 

Croton  oil  when  saponified  and  subsequently  acidified 
and  distilled  with  steam  yields  about  half  as  great  a  per- 
centage of  volatile  fatty  acids  as  does  butter  fat.  Among 
these  are  formic,  acetic,  and  valerianic  acids,  which  are  not 
found  in  butter  fat. 

Castor  oil  is  derived  from  the  castor  bean.  It  consists 
mainly  of  the  glyceride  of  ricinoleic  acid.  The  latter 
contains  eighteen  carbon  atoms  and  one  double  bond,  but 
in  addition  it  shows  the  reactions  of  a  secondary  alcohol, 
e.g.  it  forms  an  acetyl  derivative  with  acetic  anhydride, 
and  yields  an  ester,  ricinoleic  sulphonic  acid,  when  treated 
with  concentrated  sulphuric  acid.  The  latter  compound 
is  used  in  the  Turkey-red  industry.  The  structural 
formula  of  ricinoleic  acid  is  represented  as  follows : 

CH3— (CH2)6— CHOH— CH  =  CH  —  (CH2)7— COOH 

A  distinguishing  property  of  castor  oil  is  its  insolubility 
in  petroleum  ether.  It  is  likewise  the  heaviest  of  the  fats, 


178     Organic  Chemistry  for  Students  of  Medicine 

sp.  gr.  .960-.968.  Other  fats  range  in  specific  gravity 
from  .850  to  .950. 

91.  Properties  of  the  Fats.  —  Since  the  natural  fats  do 
not  represent  individual  chemical  compounds,  but  mixtures 
of  several  kinds,  their  physical  properties  depend  upon  the 
proportions  in  which  they  are  mixed,  and  especially  on  the 
content  of  olein.  They  are  insoluble  in  water,  but  slightly 
soluble  in  cold  alcohol.  They  are  readily  soluble  in  ether, 
petroleum  ether,  benzene,  chloroform,  and  in  other  solvents. 

The  fats  can  be  heated  to  200-250°  without  undergoing 
any  essential  change,  but  above  this  temperature  they 
evolve  the  irritating  vapors  of  acrolein  (CH2  =  CH — CHO), 
which  causes  profuse  secretion  of  tears.  This  has  its 
origin  from  glycerol,  from  which  it  is  formed  by  the 
loss  of  two  molecules  of  water  (85).  This  test  is  best 
carried  out  by  heating  the  fat  with  potassium  bisulphate 
(KHSO*).  This  acrolein  test  serves  to  distinguish  the 
fats  from  the  mineral  oils,  oily  esters,  and  other  substances 
having  the  physical  properties  of  fats  or  oils. 

The  commercial  fats  on  keeping  become  rancid.  This  is 
due  to  the  action  of  the  oxygen  of  the  air,  especially  in  the 
presence  of  light,  which  greatly  accelerates  their  oxidation. 
In  the  process  of  becoming  rancid  the  neutral  fats  become 
acid  in  reaction.  Fats,  especially  from  plant  sources,  are 
liable  to  become  acid  in  reaction  owing  to  their  containing 
the  enzyme  lipase,  which  accelerates  the  hydrolysis  of 
esters  into  alcohol  and  acid.  In  part  the  rancidity  of  im- 
pure fats  is  brought  about  by  the  action  of  bacteria  on 
the  proteins,  carbohydrates,  etc.,  with  which  they  are 
contaminated. 


The  Fats,  Waxes,  and  Related  Compounds     179 

The  fats  are  all  saponifiable  (hydrolyzable),  as  are  other 
esters : 

CH2— OOCi6H3i      HOH    CH2OH 

I  I 

CH— OOCi6H3i  +  HOH=CHOH  +  3C15H3oCOOH 

Palmitic  acid 

CH2— OOCi6H3i      HOH    CH2OH 

Tripalmitin  Water          Glycerol 

Hydrolysis  can  be  effected  by  heating  with  water  alone 
under  pressure,  but  takes  place  slowly  because  of  the  great 
insolubility  of  fats  in  water.  Both  acids  and  alkalies 
greatly  accelerate  the  reaction.  Technically  enormous 
quantities  of  fats  are  saponified  by  means  of  sodium  hy- 
droxide for  the  preparation  of  soap,  and  for  the  produc- 
tion of  glycerol  (glycerine).  In  the  laboratory  fats  are 
usually  saponified  with  an  alcoholic  solution  of  'potas- 
sium hydroxide,  in  which  the  fats  are  much  more  solu- 
ble than  in  water.  Their  solution  greatly  facilitates  the 
reaction. 

92.  Soaps.  —  Soap  is  made  by  boiling  the  fats  with  a 
solution  of  sodium  hydroxide  until  saponification  is  com- 
plete. Sodium  soaps  are  readily  soluble  in  water,  but  not 
in  strong  brine,  so  common  salt  is  added  to  precipitate  the 
soaps.  "The  solution  from  which  the  soap  separates  con- 
tains the  excess  of  lye  (NaOH)  together  with  the  glycerol 
formed  in  saponification.  From  the  evaporated  residue 
of  this  solution  glycerol  is  prepared  by  distillation  under 
diminished  pressure.  The  soap,  which  has  been  precipi- 
tated in  a  flaky  form,  is  separated,  melted,  and  cast  in 
molds. 


180     Organic  Chemistry  for  Students  of  Medicine 

Many  antiseptic  substances,  such  as  carbolic  acid, 
salicylic  acid,  or  cresol,  thymol,  tar,  sulphur,  naphthalene, 
camphor,  mercury,  etc.,  are  added  to  soap.  The  finer 
grades  are  usually  perfumed  and  frequently  colored. 
White  Castile  soap  is  made  of  olive  oil  and  sodium  hy- 
droxide. It  is  strongly  alkaline.  Green  soap  is  made 
from  linseed  oil  and  postassium  hydroxide,  and  is  therefore 
principally  potassium  linolate  and  linoleate.  Lead  soap 
or  lead  plaster  is  prepared  by  saponifying  olive  oil  with  lead 
oxide.  It  is  yellowish  white,  pliable  and  tenacious.  It  is 
insoluble  in  water,  but  soluble  in  chloroform  and  in  ben- 
zene. 

Ordinary  soaps  are  crystalline,  and  the  cheaper  grades 
frequently  contain  rosin,  sodium  silicate,  etc.  The  trans- 
parent soaps  are  made  by  dissolving  crystalline  soap  in 
alcohol  and  then  evaporating  most  of  the  solvent.  They 
are  in  the  colloidal  state  and  owe  their  transparency  to  this 
cause. 

Physiology  of  the  Fats  and  Soaps.  —  The  body  fat  of 
animals  is  in  part  derived  directly  from  the  food,  since 
peculiar  fatty  acids  not  found  in  the  body  fat  unless  con- 
tained in  the  food  are  deposited  in  the  fat  of  the  tissues. 
Carefully  conducted  experiments  have  shown  that  pigs  and 
geese  may  accumulate  much  more  fat  in  their  bodies  during 
the  experimental  period  than  was  contained  in  the  food. 
The  animal  body  is  therefore  able  to  form  fats  from  sugars 
and  from  proteins.  This  necessarily  means  that  both 
fatty  acids  and  glycerol  are  formed  from  other  compounds. 
Free  fatty  acids  are  never  found  in  the  blood,  and  when 
an  animal  is  fed  free  fatty  acids  instead  of  neutral  fats,  it 


The  Fats,  Waxes,  and  Related  Compounds     181 

forms  glycerol  to  combine  with  them  to  form  neutral  fats 
before  they  enter  the  circulation. 

Since  the  fats  are  not  soluble  in  water,  and  there  are  no 
fat  solvents  in  the  digestive  tract,  fats  are  not  capable  of 
being  absorbed  directly,  but  must  be  converted  into  water- 
soluble  products  before  absorption.  The  digestion  of  fats 
consists  in  their  hydrolysis  to  fatty  acids  and  glycerol. 
This  takes  place  in  the  intestine  under  the  influence  of  an 
enzyme,  lipase,  in  a  faintly  alkaline  solution.  The  free 
fatty  acids  at  once  combine  with  bases  to  form  soaps. 
Both  the  soaps  and  glycerol  are  water  soluble  and  absorb- 
able.  In  the  cells  lining  the  intestine  the  fatty  acids 
and  glycerol  are  recombined  to  form  neutral  fats  before 
entering  the  circulation. 

93.  The  Cleansing  Action  of  Soap.  —  The  sodium  and 
potassium  soaps  are  soluble  in  water,  and  being  the  salts 
of  very  weak  acids  they  undergo  hydrolytic  dissociation, 
that  is,  they  react  with  water  to  some  extent,  with  the 
formation  of  free  fatty  acid  and  sodium  hydroxide : 

(1)  CH3— (CH2)16— COONa 

Sodium  stearate 

^±  CH3—  (CH2)16— COO-+Na+ 

Stearate  ion 

(2)  CH3— (CH2)16— COO-  +Na+  +HOH 

Stearate  ion  Water 

^±  CH3—  (CH2)16— COOH+NaOH 

Stearic  acid 

This  reaction  is  due  to  the  fact  that  salts  of  weak  acids 
are  strongly  dissociated  while  the  weak  acids  themselves  are 
but  slightly  dissociated  into  fatty  acid  ions  and  hydrogen 


182     Organic  Chemistry  for  Students  of  Medicine 

ions.  The  acid  ions  combine  with  the  hydrogen  ions  of 
the  water  to  form  undissociated  fatty  acid  molecules. 
The  acids  thus  liberated  combine  with  a  molecule  of  soap 
and  form  insoluble  stubstances  which  give  the  milky 
appearance  to  water  solutions  of  eoap.  The  amount  of 
free  alkali  produced  depends  on  the  degree  of  dilution  of 
the  soap  solutions.  Strong  soap  solution  scarcely  causes 
the  pink  color  characterisitc  of  alkalies  with  phenol- 
phthalein,  and  the  depth  of  pink  steadily  increases  as  the 
solution  is  diluted  with  water. 

When  fats  come  into  contact  with  soap  solutions,  they 
tend  when  agitated  to  form  an  emulsion,  i.e.  the  droplets 
of  fat  break  up  into  very  fine  particles,  each  surrounded 
by  a  film  of  soap  solution  which  separates  each  drop  from 
its  fellows  and  prevents  their  union  into  larger  drops  and 
consequent  separation.  The  action  of  soap  in  removing 
grease  is  therefore  twofold  :  the  free  alkali  will  saponify  a 
part  of  the  fats  and  thus  part  will  pass  into  solution  as 
soap ;  the  remainder  is  emulsified  and  remains  permanently 
suspended  in  the  soap  solution. 

As  the  free  alkali  is  used  up  by  the  saponification  of  fats, 
more  soap  dissociates  to  replace  that  which  has  disappeared. 
Soap  therefore  serves  as  a  reserve  supply  of  alkali,  and 
in  washing  there  is  automatically  maintained  a  constant 
content  of  hydroxyl  ions  in  solution  without  at  any  time  an 
undesirably  high  content.  Soap  is  for  this  reason  superior 
to  a  free  alkali  solution  for  washing.  A  dilute  solution  of 
the  latter  would  show  a  progressive  decrease  in  hydroxyl 
ions  as  its  use  progressed. 

Soap  does  not  readily  remove  the  higher  hydrocarbons, 


The  Fats,  Waxes,  and  Related  Compounds     183 

such  as  vaseline,  unless  there  is   simultaneously  present 
some  fat  or  oil. 

94.   Methods  for  the  Characterization  of  the  Fats.  - 
The  chemical  nature  of  the  fats  is  indicated  by  their 
physical  characters*  and  by  their  behavior  toward  certain 
chemical  reagents. 

The  melting  point  and  the  temperatures  at  which  the 
fats  solidify  after  having  been  melted  serve  to  show  the 
general  nature  of  the  fats,  whether  principally  stearin  or 
palmatin,  or  containing  much  olein. 

The  acid  number  gives  the  milligrams  of  KOH  necessary 
to  neutralize  the  free  fatty  acids  contained  in  one  gram  of 
fat.  For  its  determination,  1-2  grams  of  the  fat  in  12-15 
c.c.  of  a  mixture  of  1  part  of  alcohol  and  2  part  of  ether, 
which  should  react  neutral  to  phenolphthalein  indicator, 
are  titrated,  using  this  indicator  with  a  1/10  normal  solu- 
tion of  potassium  hydroxide  in  alcohol.  Fresh  animal 
fats  are  nearly  neutral,  but  on  becoming  rancid  or  on  long 
keeping  the  acidity  rises  markedly.  This  number  gives 
an  idea  as  to  the  state  of  freshness  of  the  fats. 

Saponification  Number.  —  Since  each  molecule  of  fat  re- 
acts with  three  molecules  of  potassium  hydroxide  to  form 
glycerol  and  three  molecules  of  soap,  the  number  of  carbon 
atoms  in  the  fatty  acids  contained  in  the  fats  will  deter- 
mine whether  little  or  much  alkali  will  be  necessary  to 
saponify  a  standard  quantity  of  fat.  The  saponification  ' 
number  indicates  the  number  of  milligrams  of  potassium 
hydroxide  necessary  to  neutralize  the  fatty  acids  derived 
from  one  gram  of  fat.  It  is  determined  by  dissolving  a 
weighed  amount  of  fat  in  a  carefully  standardized  solution 


184     Organic  Chemistry  for  Students  of  Medicine 


of  potassium  hydroxide  in  alcohol,  and  heating  until 
saponification  is  complete.  Water  is  then  added  and  the 
free  alkali  in  the  solution  is  titrated  by  the  addition  of 
standard  acid  to  the  neutral  point,  using  phenolphthalein 
as  indicator.  The  difference  between  the  KOH  content  of 
the  solution  employed  to  saponify  the  fat  and  the  alkali 
remaining  unneutralized  after  the  saponification  shows 
how  much  alkali  has  been  neutralized  by  the  fatty  acids 
formed.  Essentially  this  method  is  a  determination  of  the 
molecular  weight  of  the  fat,  as  the  following  table  shows : 


, 

MOL.  WEIGHT 

SAPONIFICATION 
No. 

Butyrin                                         . 

302 

557  3 

Caproin      .    *. 

336 

436  1 

Palmatin    .     .     .     .  >,     .     .     . 

806 

2088 

Stearin       

890 

189  1 

Olein      

884 

1904 

Unsaponifiable  Residue.  —  It  is  obvious  that  the  saponi- 
fication number  can  give  reliable  data  concerning  the 
molecular  weights  of  the  fatty  acids  contained  in  the  fats, 
only  when  glycerol  is  the  only  alcohol  present  in  the  fats. 
Now  it  not  infrequently  happens  that  there  occur  with  the 
fats  certain  other  alcohols,  as  cetyl  and  octadecyl  alcohols 
and  cholesterol  (C27H43OH),  an  alcohol  of  high  molecular 
weight  which  is  structurally  very  different  from  the  higher 
alcohols  derived  from  the  aliphatic  hydrocarbons  (99). 
These  occur  free  or  in  ester  linkage  with  fatty  acids. 
Cholesterol  possesses  physical  properties  very  similar  to 


The  Fats,  Waxes,  and  Related  Compounds     185 

the  fats  and  fatty  acids,  and  occurs  free  and  as  esters 
almost  universally  distributed  in  animal  and  plant  tissues. 
Since  these  alcohols  have  molecular  weights  of  242,  270 
and  384  respectively,  whereas  that  of  glycerol  is  but  92, 
the  saponification  number  can  be  properly  interpreted 
only  when  the  content  of  these  higher  alcohols  is  known. 

These  alcohols  are  collectively  estimated  by  repeatedly 
shaking  with  petroleum  ether  the  solution  of  the  soaps, 
glycerol,  and  higher  alcohols  obtained  in  the  determina- 
tion of  the  saponification  number  after  again  making  it 
alkaline  after  the  titration.  Petroleum  ether  does  not 
dissolve  soaps,  glycerol,  or  potassium  hydroxide,  but 
readily  dissolves  the  higher  alcohols  in  question.  After 
separating  the  petroleum  ether,  filtering,  and  evaporating 
it,  and  again  taking  up  the  residue  of  higher  alcohols  in  a 
fat  solvent  such  as  ether,  the  solution  is  filtered,  and  the 
solvent  evaporated  in  a  weighed  dish.  The  residue  is 
weighed  after  keeping  the  dish  in  a  desiccator  until  its 
weight  is  constant.  This  weight  represents  the  higher 
alcohols  which  were  present  in  the  sample  of  fat. 

A  few  typical  values  of  the  higher  alcohols  in  some  com- 
mon fats  will  illustrate  the  importance  of  this  determina- 
tion. UNSAPONIFIABLE  MATTER 

Linseed  oil  .42-1.0 

Olive  oil  .46-1.0 

Castor  oil  .30-.40 

Corn  oil  1.35-2.90 

Wheat  oil  4.45 
Human  fat  .33 

Lard  .30-.40 


186     Organic  Chemistry  for  Students  of  Medicine 

Shark  liver  oil  7.0-10.5 

Sperm  oil  37.0-41.0 

Beeswax  52.0-56.0 

The  Iodine  Number.  —  The  relative  content  of  saturated 
and  unsaturated  fatty  acids  in  fats  is  determined  by  the 
capacity  of  the  fats  to  absorb  iodjne.  As  an  example 
of  the  determination  of  this  value,  the  Hubl  method  will 
be  described : 

(1)  A  standard  solution  of  iodine  containing  25  grams  of 
iodine  and  30  grams  of  mercuric  chloride  dissolved  in 
500  c.c.  of  alcohol,  free  from  fusel  oil. 

(2)  A  solution  of  sodium  thiosulphate  containing  24 
grams  of  the  salt  per  liter.     This  solution  is  standardized 
by  determining  the  number  of  milligrams  of  iodine  which 
is  reduced  by  a  cubic  centimeter  of  the  solution. 

The  sample  of  fat,  .3  to  .4  gram  of  olein-rich  fats  or  .8 
to  1  gram  of  solid  fats,  is  weighed  into  a  glass  stoppered 
bottle  and  dissolved  in  15-25  c.c.  of  chloroform.  It  is  then 
heated  with  25  c.c.  of  the  iodine  solution.  After  6  to  10 
hours  20  c.c.  of  a  10  %  potassium  iodide  solution  is 
added,  the  whole  diluted  with  water,  and  the  unabsorbed 
iodine  is  titrated  by  means  of  the  sodium  thiosulphate 
solution.  The  KI  is  added  to  prevent  the  separation  of 
iodine  in  the  solid  state  on  dilution  with  water. 

The  following  values  illustrate  the  iodine  values  for 
several  kinds  of  fats : 

IODINE  NUMBERS  PURE  FATS 

Olein  86.2 

Linolein  173.6 

Linolenin  262.2 


The  Fats,  Waxes,  and  Related  Compounds     187 

IODINE  NUMBERS  OF  NATURAL  FATS 

Linseed  oil  170-200 

Hempseed  oil  145-150 
Almond  oil                        -       93-97 

Olive  oil  80-88 

Palm  oil  51 
Coconut  gil  8-9 

Tallow  (beef)  38-45 

Tallow  (mutton)  35-45 

Lard  50-70 

Butter  26-38 

Reichert-Meissl  Number  (Volatile  fatty  acid  number).  - 
It  has  already  been  stated  that  certain  fats  contain  much 
larger  amounts  of  the  fatty  acids  of  lower  molecular  weight, 
as  butyrin,  caproin,  etc.  These  acids,  after  saponifica- 
tion  of  the  fat  with  an  alkali  and  subsequent  acidification 
with  a  non-volatile  mineral  acid,  pass  over  with  steam 
when  the  mixture  of  fatty  acids  and  water  is  distilled. 
The  distillate  is  titrated  with  standard  alkali,  using  phenol- 
phthalein  as  indicator.  The  number  of  cubic  centimeters  of 
1/10  normal  alkali  required  to  neutralize  the  volatile  acids 
from  5  grams  of  fat  constitute  the  Reichert-Meissl  number. 

The  values  of  the  Reichert-Meissl  number  for  some  of 
the  more  important  fats  are  as  follows : 

Linseed  oil    0.0  Palm  oil  5.0-7.0 

Olive  oil        0.6  Coconut  oil  6.5-7.0 

Lard  .7  Croton  oil  12.-13.5 

Tallow  .5  Butter  fat  21-33.0 

Goose  fat    .2-.2 


188     Organic  Chemistry  for  Students  of  Medicine 

This  method  of  examination  is  of  great  service  for  the 
examination  of  butter  for  adulteration.  No  other  fat 
approximates  the  high  value  of  butter  fat  in  volatile  fatty 
acids,  and  the  lowering  of  this  value  by  the  addition  of 
vegetable  fats  or  the  body  fats  of  animals  is  readily  de- 
tected. 

Acetyl  Number. — Very  few  of  the  natural  fats  contain 
hydroxylated  fatty  acids.  Chief  among  these  is  castor 
oil,  which  in  ricinoleic  acid  contains  a  secondary  alcohol 
group  (90) .  The  amount  of  hydroxy  fatty  acids  is  arrived 
at  through  treatment  of  the  fat  with  acetic  anhydride 
(64)  and  heat,  whereby  the  hydroxyl  group  of  the  fat 
forms  an  acetic  ester : 

R  v  /CO— CH3        R-^ 

>CHOH+0(  ->         HC— OOC— CH3 

R'/  \CO— CH3       R'-- 

+  CH3— COOH 


Acetic  anhydride 


Such  esters  are  stable  to  boiling  water,  and  the  excess  of 
acetic  anhydride  can  be  converted  into  acetic  acid  by 
boiling  : 

(CH3— COO)2O  +  H2O  =  2CH3— COOH 

The  acetylated  fats  are  then  separated  mechanically, 
since  they  are  insoluble  in  water  and  form  a  layer.  After 
washing  these  free  from  acid  reaction  and  collecting  on  a 
filter  paper  they  are  dried  at  100°  to  constant  weight.  A 
carefully  weighed  sample  (2-5  grams)  is  then  saponified 
with  an  excess  of  carefully  measured  standard  solution 
of  alcoholic  potassium  hydroxide  N/10.  When  saponi- 
fication  is  complete,  the  same  volume  of  N/10  acid  is 


The  Fats,  Waxes,  and  Related  Compounds     189 

added  as  was  added  of  N/10  alkali  in  the  saponification 
and  the  solution  warmed.  The  aqueous  layer  is  then 
siphoned  off  through  filter  paper  and  the  remaining  oil 
is  washed  until  all  soluble  acids  are  washed  out.  The 
filtrate  and  washings  are  titrated  with  N/10  alkali,  using 
phenolphthalein  as  an  indicator.  Soluble  fatty  acids 
must  be  determined  separately  and  their  amount  deducted 
from  the  value  found. 

The  following  table  shows  the  values  for  the  acetyl 
number  of  some  common  fats : 

Linseed  oil           4.0  Beeswax  15.2 

Olive  oil  10.5  Cod  liver  oil  4.8 

Palm  oil  18.0  Shark  liver  oil  12.0 

Lard                     2.6  Seal  fat  16.5 

Tallow  (beef)       2.5-8.6  Spermaceti  4.5 

Wool  wax  23.0 

The  elaidin  test  depends  upon  the  fact  that  oleic  acid 
changes  from  the  cis  to  the  trans  form  (86)  with  a  marked 
rise  in  melting  point  when  treated  with  nitrous  oxide. 
The  test  is  carried  out  by  placing  the  oil  (10  c.c.)  in  a  test 
tube  with  nitric  acid  (.5  c.c.)  underneath  it,  and  placing 
in  the  acid  a  piece  of  copper  (.2  gm.).  If  much  oleic  acid 
is  present,  the  fat  will  have  become  solid  at  the  temper- 
ature of  25°  by  the  following  day.  Fats  having  two  or 
three  double  bonds  do  not  give  this  test. 

The  Hexabromide  Test.  —  Dibrom  and  tetrabrom  stearic 
acids  result  from  the  absorption  of  bromine  by  oleic  and 
linolic  acids  or  their  fats.  Both  of  these  are  soluble  in 
ether.  Linolenic  acid  having  three  double  bonds,  yields  a 


190     Organic  Chemistry  for  Students  of  Medicine 

hexabrom  derivative,  which  is  insoluble  in  ether.  The 
test  is  of  value  therefore  in  detecting  linolenic  acid  and  its 
fats.  One  to  two  c.c.  of  fat  are  treated  with  40  c.c.  of  ether 
and  cooled  to  5°.  Bromine  is  then  added  until  the  brown 
color  is  permanent.  Linolenic  acid-containing  fats  yield 
a  precipitate  within  three  hours.  It  can  be  filtered  and 
washed  with  acetic  acid,  alcohol,  and  ether,  and  weighed 
after  keeping  in  a  desiccator  to  constant  weight. 

Separation  of  oleic  acid  as  the  lead  soap.  The  lead  soap 
of  oleic  acid  is  soluble  in  ether  and  in  benzene,  while  the 
corresponding  soaps  of  stearic  and  palmitic  acids  are 
practically  insoluble  in  these  solvents.  This  property  is 
made  use  of  in  effecting  their  separation. 

95.  The  Waxes.  —  The  surfaces  of  all  organisms,  both 
animals  and  plants,  are  covered  with  a  layer  of  wax,  which 
also  permeates  the  external  layers  of  cells.  There  are 
several  kinds  of  waxes;  all,  however,  are  esters  derived 
from  one  of  the  higher  fatty  acids  and  a  monatomic  alcohol 
of  high  molecular  weight.  They  have  the  common  prop- 
erty of  being  more  or  less  solid  at  ordinary  temperatures, 
but  on  warming  they  soften  and  can  be  kneaded.  They 
melt  at  60  to  80°.  The  waxes  are  wholly  insoluble  in 
water,  but  soluble  in  boiling  alcohol,  and  less  soluble  in 
ether.  They  also  dissolve  in  chloroform  and  turpentine. 
Like  fats  they  produce  a  transparent  spot  when  melted  on 
paper,  and  confer  a  shiny  appearance  on  objects  coated 
with  them.  Water  does  not  penetrate  even  a  thin  wax 
layer.  They  are  not  altered  by  light  or  air,  or  by  bac- 
teria or  molds,  and  are  proof  against  changes  similar  to 
rancidity.  Furthermore  waxes  are  among  the  poorest  heat 


The  Fats,  Waxes,  and  Related  Compounds     191 

conductors  known.  Their  composition  is,  approximately, 
carbon,  80%;  hydrogen,  12-13%;  and  oxygen,  7-8%. 

These  remarkable  properties  are  of  the  very  greatest 
biological  importance.  They  prevent  wetting  of  the  tissues 
of  animals  and  plants,  and  in  the  case  of  plants,  eggs  of 
insects,  etc.,  exposed  to  very  hot,  dry  atmospheric  condi- 
tions, the  waxy  covering  prevents  excessive  desiccation 
through  evaporation.  This  layer  also  serves  as  an  effect- 
ive barrier  against  the  invasion  of  the  tissues  by  bacteria, 
and  as  a  protection  against  changes  of  temperature. 

While  waxes  form  a  layer  covering  the  green  parts  of  all 
plants,  they  are  found  in  much  greater  abundance  on  some 
plants  than  others.  Carnauba  wax  is  found  on  the  leaves 
of  the  Brazilian  palm,  Copernicia  cerifera.  It  is  used  for 
candle  making,  polishes,  wax  varnishes,  etc.  It  consists 
of  ceryl  alcohol,  €2511540,  and  myricyl  alcohol,  as  esters  of 
cerotic  and  lignoceric  acids,  C26H52O2  and  C24H48O2,  re- 
spectively. The  waxes  of  the  graminese  contain  princi- 
pally myricyl  alcohol  and  melissic  acid,  CsoHeoC^.  Certain 
other  waxes  of  plant  origin  contain  palmitic  acid  as  ester 
with  the  alcohols  named,  but  cerotic,  myristic,  and  melissic 
acids  are  most  common.  In  certain  cases,  as  Japan  wax, 
obtained  from  several  species  of  Rhus,  the  waxes  are  re- 
placed by  the  hard  fat  palmitin.  Myrtleberry  wax  is 
likewise  principally  palmitin.  These  are  therefore  not 
true  waxes. 

Among  the  animal  waxes  of  great  importance  are  those 
produced  by  various  insects.  They  serve  to  protect  the 
eggs  and  larvae  against  moisture  and  loss  of  heat.  Chinese 
wax  produced  by  a  coccus  is  ceryl  cerotate ;  psylla  wax, 


192     Organic  Chemistry  for  Students  of  Medicine 

produced  by  a  leaf  louse  in  Finland,  is  the  ester  formed  of 
psylla  alcohol,  CssHeyOH,  and  psylla  acid,  CasHeeOz.  Bees- 
wax consists  principally  of  myricyl  alcohol  and  cerotic 
and  melissic  acids  in  ester  combination.  It  is  employed 
by  the  honeybees  for  protecting  their  eggs  and  larvae 
against  cold  and  also  for  honeycomb.  It  also  contains 
impurities  gathered  from  plants. 

The  gland  at  the  base  of  the  tail  in  birds  secretes  a 
liquid  wax  which  the  birds  spread  over  their  feathers 
to  render  them  waterproof  and  soft.  This  wax  consists 
of  palmitic,  stearic,  and  oleic  acid  esters  of  octadecyl 
alcohol,  Ci8H38O. 

Spermaceti  is  a  wax,  principally  cetyl  palmitate,  which  is 
obtained  from  a  cavity  in  the  head  of  the  sperm  whale. 
From  this  cavity  a  canal  runs  to  the  tail  and  branches 
communicate  with  pockets  in  the  panniculus.  The  wax 
is  thus  conveyed  to  all  parts  of  the  skin,  which  it  permeates 
and  protects  from  the  action  of  the  sea  water.  Similar 
esters  are  found  in  whale  oil  and  in  the  oil  from  dolphins. 

The  production  of  spermaceti  is  closely  analogous  to  the 
secretion  of  wax  by  the  tail  glands  of  birds  and  to  the  uni- 
versal distribution  of  the  sebaceous  glands  in  the  skin  of 
the  higher  animals  which  produce  an  oily  secretion  of 
liquid  wax  which  protects  the  skin  and  hair. 

Wool  wax  (lanolin),  the  natural  covering  of  sheep's 
wool,  contains  much  cholesterol  and  oxycholesterol  in  the 
free  state,  and  also  as  esters  of  several  fatty  acids,  espe- 
cially myristic,  cerotic,  and  lanoceric.  Wool  wax  also  con- 
tains other  higher  alcohols,  as  carnaubyl,  C24H60O,  and 
lanolin  alcohol,  C^H^O. 


The  Fats,  Waxes,  and  Related  Compounds     193 

96.  Lecithins  and  other  Phosphatides.  —  As  constitu- 
ents of  every  living  cell,  both  animal  and  plant,  there 
occur  compounds  closely  related  to  the  fats,  called  lecithins. 
These  on  hydrolysis  yield  one  molecule  of  glycerol,  two 
of  fatty  acid,  one  of  orthophosphoric  acid  (HsPOO,  and  one 
of  choline  (48). 

Glycerol  forms  with  phosphoric  acid  an  ester,  glycero- 
phosphoric  acid : 

CH2OH  CH2OH 

I  I 

CHOH  =   CHOH 

CH2  |OH+H|  Q— RO(OH)2         CH2— Q— PO(OH)2 

Glycerophosphoric  acid 

Lecithins  are  regarded  as  complexes  of  the  following 

structure : 

^»  ;.  ^  • 

CH2— OOC— R  1 

|  Fatty  aeid  radicals 
CH  — OQC— R  J 


Glycerol 
residue 


CB 

:A  i 


-°\      1 

>P=O 
TTQ/    I          r  Phosphoric  acid  radical 


Choline  group 


Little  is  known  with  certainty  of  the  chemistry  of  the 
various  lecithins.     It  is  evident  that  different  fatty  acids 


194     Organic  Chemistry  for  Students  of  Medicine 

in  the  molecule  would  lead  to  lecithins  of  different  proper- 
ties. Furthermore  there  is  the  possibility  that  two  differ- 
ent fatty  acids  may  be  linked  in  the  same  molecule,  forming 
mixed  lecithins.  Isomerism  is  likewise  possible  due  to  the 
different  linking  of  the  phosphoric  acid-choline  group  : 

CH2O— fatty  acid  A  CH2O— fatty  acid  A 

CHO— fatty  acid  A  or  CHO— phosphoric 

acid-choline 
CH2O — phosphoric  acid-choline  CH2O — fatty  acid  A 

The  investigation  of  this  class  of  compounds  presents 
almost  insurmountable  difficulties.  They  are  of  a  waxy 
nature,  and  do  not  form  compounds  with  other  substances 
which  can  be  crystallized,  for  purposes  of  purification,  and 
they  cannot  be  distilled  without  decomposition,  and  have 
no  definite  melting  point.  There  is  therefore  no  criterion 
by  which  to  judge  when  one  is  in  possession  of  an  indi- 
vidual chemical  compound  or  is  dealing  with  a  mixture, 
except  constancy  of  composition  of  the  material  after 
repeated  solution  and  precipitation  of  the  lecithin.  This 
is  carried  out  in  most  instances  by  dissolving  the  lecithin 
in  ether  and  pouring  the  solution  into  a  large  volume  of 
acetone  in  which  lecithin  is  insoluble.  The  precipitates 
are  always  amorphous.  When  on  repeating  this  method  of 
purification  the  precipitate  is  found  to  contain  the  same 
percentages  of  nitrogen  and  phosphorus,  these  being  the 
easiest  elements  to  determine  quantitatively,  the  assump- 
tion is  often  made  that  the  precipitated  material  represents 
a  chemical  individual.  Instances  are  known  however  in 
which  two  substances  precipitate  in  fairly  constant  pro- 


The  Fats,  Waxes,  and  Related  Compounds     195 

portions  under  such  conditions,  so  that  such  a  method  of 
purification  cannot  inspire  'much  confidence. 

Among  the  compounds  formed  by  lecithin  which  have  a 
crystalline  structure,  and  which  are  serviceable  for  its 
purification,  are  the  cadmium  chloride  double  salt,  which 
can  be  crystallized  from  a  mixture  of  benzene  and  alcohol. 

The  lack  of  satisfactory  criteria  of  purity  for  compounds 
of  this  class  has  rendered  their  investigation  uninviting 
as  compared  with  other  lines  of  study.  This  in  a  measure 
accounts  for  the  paucity  of  our  knowledge  of  these  com- 
pounds. 

Birds  when  fed  certain  fat-free  and  lecithin-free  foods 
can  grow  and  produce  eggs  containing  much  larger 
amounts  of  lecithins  than  the  bodies  of  the  birds  contained 
at  the  beginning  of  the  experiment.  The  lecithin  complex 
is  therefore  synthesized  in  the  animal  cells  from  its  con- 
stituents. It  has  been  pointed  out  (92)  that  fatty  acids 
and  glycerol  can  be  formed  by  the  animal  body  from  sugars 
and  proteins.  The  synthesis  of  lecithin  by  birds  shows 
that  the  choline  complex  is  also  synthesized  by  the  animal 
cells.  Diets  on  which  birds  accomplished  this  synthesis 
contained  neither  glycol  nor  trimethylamine.  The  steps 
by  which  choline  is  formed  are  not  clearly  understood,  but 
it  is  evident  that  the  animal  cells  can,  under  certain  condi- 
tions, form  methylated  nitrogen  compounds,  as  trimethyl- 
amine, as  it  is  known  to  do  with  tellurium  and  selenium  (6). 


Neurine,  ,       trimethyl-vinyl- 

OH 

ammonium  hydroxide.—  We  are  by  no  means  certain  that 


196     Organic  Chemistry  for  Students  of  Medicine 

choline  is  the  only  nitrogen  base  contained  in  the  natural 
compounds  of  the  lecithin  type.  Thudicum,  a  worker  of 
distinction  in  this  field,  states  that  from  certain  phospha- 
tides  of  the  brain  (cephalin)  he  obtained  neurine.  It  is 
highly  probable  that  bases  other  than  choline  exist  in 
lecithins.  Neurine  is  derived  from  choline  by  the  loss  of 
a  molecule  of  water : 

CH2OH  CH2 

-H2Q   I 

CH2— N  » (CH3)3  "         *  CH— N  =  (CH3)3 


)H  OH 

Choline  Neurine 

Neurine  is  much  more  toxic  than  choline. 
Choline,  being  an  alcohol  as  well  as  a  base,  can  yield  an 
aldehyde  on  oxidation : 

CH2OH  CHO 

+0      I 


CH2— N  =  (CH3)3  CH2— N  =  (CH3) 

OH  OH 

Muscarine 

As  an  alcohol,  choline  yields  esters  with  various  acids. 
These  in  general  possess  pronounced  pharmacological  prop- 
erties, being  much  more  toxic  than  choline  itself. 

97.  Muscarine,  a  highly  toxic  substance,  occurs  in 
some  of  the  poisonous  mushrooms,  but  appears  not  to  be 
toxic  enough  to  account  for  all  of  their  poisonous  prop- 
erties. 


The  Fats,  Waxes,  and  Related  Compounds     197 

Other  phosphatides  (compounds  yielding  fatty  acids, 
glycerol,  some  nitrogen-containing  base,  and  phosphoric 
acid)  have  been  described,  among  them  cephalin,  the 
acids  of  which  are  more  unsaturated  than  those  of  ordinary 
lecithins.  The  base  is  apparently  not  choline.  It  is  not 
as  yet  satisfactorily  studied. 

98.  The  Cerebrosides.  —  There  is  found  in  the  nervous 
tissue  a  group  of  substances  which  contain  no  phosphorus, 
but  yield    on    hydrolysis  a  nitrogen-containing  base  of 
unknown  chemical  nature,  a  sugar  (galactose),  and  a  fatty 
acid.     They  are  not  found  in  embryonic  nervous  tissues, 
but  develop  during  medullation.     Two  such  compounds 
are  phrenosin  and  kerasin.     They  still  need  further  study 
to  reveal  their  chemical  structure. 

99.  Sterols.  —  The   brain   at   different   ages   contains 
varying  amounts  of  cholesterol  (4-9  %)  and  possibly  several 
more  or  less  closely  related  compounds  of  this  nature.     Its 
content  increases  with  age.     As  stated  under  waxes  (95) 
cholesterol  is  an  alcohol  of  high  molecular  weight.     Its 
formula  is  represented  by  C27H460.     Several  of  its  esters 
are  known.     Its  structure  has  been  in  part  elucidated. 
Its  alcohol  group  is  a  secondary  one,  since  it  oxidizes  to  a 
ketone.     It  also  contains  a  double  bond,  as  shown  by  its 
forming  an  addition  product  with  bromine  or  iodine.     The 
structure  of  the  rest  of  the  molecule  is  not  yet  established. 
Compounds  closely  related  to  cholesterol  are  found  in  the 
fats  of  plants.     These  are  called  phytosterols. 

Cholesterol  is  a  crystalline  solid,  insoluble  in  water, 
sparingly  soluble  in  cold,  but  readily  in  hot,  alcohol,  ether, 
acetone,  chloroform,  and  other  organic  solvents.  Choles- 


198    Organic  Chemistry  for  Students  of  Medicine 

terol  melts  at  147  °.  It  forms  an  acetyl  derivative  (ester) 
when  heated  with  acetic  anhydride,  which  melts  at  114° 
and  is  useful  in  identifying  cholesterol. 

Cholesterol  forms  with  a  natural  glycoside,  digitonin, 
a  compound  sparingly  soluble  in  95  %  alcohol.  It  is 
frequently  precipitated  in  this  form  and  weighed  in  its 
quantitative  estimation. 

An  isocholesterol  has  been  described  as  occurring  in 
lanolin,  and  a  derivative  called  coprosterol  has  been  iso- 
lated from  feces.  It  has  no  double  bond  and  results  from 
the  reduction  of  cholesterol,  due  to  bacterial  action. 


CHAPTER   IX 
THE   DIBASIC   ACIDS 

100.  It  has  been  shown  how  hydrocyanic  acid  reacts 
with  water,  forming  ammonium  formate  (50).  In  fact, 
solutions  of  HCN  are  unstable,  tending  to  react  with 
water :  RCN  +  2  J^Q  =  HCOONH4 

Hydrocyanic  acid  is  therefore  the  nitrile  of  formic  acid. 

CN 
Cyanogen,  |  ,  on  the  other  hand,  when  boiled  with 

CN 
acids  reacts  with  water  to  form  oxalic  acid : 

CN        COONH4   COOH 
|   +  4  H20  =  |      =|     +  2  NH3 
CN        COONH4   COOH 

Ammonium  oxalate 

Cyanogen  has  therefore  the  double  formula  indicated. 
Oxalic  acid  occurs  in  nature  in  many  plants  —  rhubarb, 
sorrel,  etc.  It  is  deposited  as  its  salt,  calcium  oxalate,  in 
the  leaves  and  cells.  These  crystals  have  the  appearance 
of  envelopes.  Oxalic  acid  is  of  great  importance  in  ana- 
lytical chemistry.  By  reason  of  its  possession  of  two  car- 
boxy  1  groups  it  forms  two  series  of  salts,  acid  and  neutral. 
The  most  important  salts  are  the  acid  potassium  and  the 
neutral  calcium  salt.  The  former  is  present  in  the  juices 

199 


200     Organic  Chemistry  for  Students  of  Medicine 

of  many  plants,  from  which  it  is  obtained  in  a  crystalline 
form  on  evaporation.  The  calcium  salt  is  so  slightly 
soluble  in  water  and  in  dilute  acetic  acid  that  it  is  em- 
ployed for  the  quantitative  estimation  of  calcium. 

The  salt  of  urea  with  oxalic  acid  is  soluble  in  23  parts 
of  water  and  in  60  parts  of  alcohol.  This  compound  has 
been  employed  for  the  isolation  of  urea  from  urine. 

With  great  care  and  with  proper  conditions  oxalic  acid 
can  be  decomposed  by  heat  into  formic  acid  and  carbon 
dioxide  :  COOH 


COOH 

On  heating  strongly  the  formic  acid  decomposes  into 
water  and  carbon  monoxide.  The  calcium  salt  on  being 
heated  forms  calcium  carbonate  (calcium  oxide  +  carbon 
dioxide)  and  carbon  monoxide  : 

coo\ 

I         )Ca=CaO+C02+CO. 
COCK 

Oxalic  acid  can  also  be  formed  by  quickly  raising  sodium 
formate  to  a  high  temperature. 

2  HCOONa  =  H2  +  (COONa)2 

Dehydrating  agents  such  as  concentrated  sulphuric  acid 
decompose  oxalic  acid,  forming  carbon  monoxide,  carbon 
dioxide,  and  water.  This  is  a  convenient  way  of  preparing 
carbon  monoxide.  Characteristic  of  oxalic  acid  is  its 
conversion  into  volatile  products  without  charring  when 
heated  on  platinum,  and  also  the  absence  of  charring  when 
it  is  heated  with  concentrated  sulphuric  acid.  In  dilute 


The  Dibasic  Acids  201 

sulphuric  acid  it  is  easily  oxidized  by  potassium  perman- 
ganate solution.  This  decolorization  of  dilute  permanga- 
nate solutions  is  caused  by  many  other  compounds.  It 
is  also  formed  by  the  oxidation  of  many  organic  substances 
such  as  starch,  wood,  etc.  It  results  from  the  oxidation  of 
alcohol  by  potassium  permanganate.  The  various  stages 
through  which  the  oxidation  may  pass  are  illustrated  by 
the  following  scheme  : 

CH3      CH3      CH3     CH2OH    CHO 

|     +0  |     +0  |    +0  I     +0  I 
CH2OH  -  >  CHO    *  COOH  ~  *  COOH  ~~J  COOH 

+  0 
CH2OH    CHO     CHO  S*         COOH 

I       ±2  1       ±2  1 

CH2OH~  >CH2OH~  *CHO  COOH 


This  series  of  compounds  illustrates  what  not  infre- 
quently happens  in  reactions  involving  the  oxidation  of 
organic  compounds.  The  reaction  does  not  proceed  with 
the  formation  of  the  end  products  indicated  by  the  simple 
equations  usually  written,  but  stepwise,  and  with  the 
formation  of  a  number  of  oxidation  products.  Only  be- 
cause the  oxalic  acid  is  highly  resistant  to  further  oxida- 
tion under  certain  conditions  does  the  reaction  stop  at 
this  point  instead  of  going  on  to  carbon  dioxide  and  water. 
In  many  synthetic  reactions  the  same  type  of  change 
occurs,  viz.  there  is  a  principal  reaction  accompanied  by 
a  number  of  side  reactions  which  form  by-products  and 
diminish  the  yield  of  the  desired  substance.  By  allowing 


202     Organic  Chemistry  for  Students  of  Medicine 

the  reaction  to  proceed  for  but  a  short  time  or  conducting 
it  at  low  temperatures,  etc.,  the  intermediary  compounds 
can  frequently  be  accumulated  in  greater  amounts. 

Properties  of  Oxalic  Acid.  —  It  crystallizes  from  water 
in  colorless  prisms  containing  two  molecules  of  water  of 
crystallization.  In  this  form  it  melts  at  101.5°.  On 
being  heated  for  a  time  at  100°  it  loses  its  water  and  forms 
a  white  powder  of  anhydrous  acid  which  melts  at  189°.  It 
dissolves  readily  in  alcohol  but  very  slightly  in  ether,  and 
is  insoluble  in  chloroform,  petroleum  ether,  and  benzene. 

Oxalic  acid  is  a  strong  acid.  On  evaporating  a  solution 
of  sodium  chloride  with  oxalic  acid,  sodium  oxalate  crys- 
tallizes out,  and  on  heating  a  mixture  of  sodium  chloride 
and  oxalic  acid,  hydrochloric  acid  gas  is  evolved.  It  is 
a  corrosive  poison  which  acts  very  quickly.  In  general 
it  cannot  serve  as  a  source  of  carbon  for  molds  or  bacteria, 
but  there  are  some  observations  tending  to  show  that  cer- 
tain organisms  can  so  use  it.  Oxalic  acid  is  produced  from 
sugars  by  certain  molds. 

In  the  higher  animals  oxalic  acid  is  burned  to  but  very 
slight  extent. 

The  dibasic  acids  form  esters,  amides,  etc.,  as  do  the 
monobasic  acids.  There  is  in  each  case,  however,  a  deriva- 
tive possible  in  which  but  one  carboxyl  is  substituted,  as 
well  as  one  derived  by  the  reaction  of  both  acid  radicles. 

COOH 

101.   Malonic  Acid,  CH2     . — This  acid  results  from  the 
COOH 


The  Dibasic  Acids  203 

• 

nitrile  which  is  formed  by  the  reaction  of  monochloracetic 
acid  with  potassium  cyanide : 

CN  COOH 

CH2-C1  |  | 

+  KCN=CH2    +2H2O  =  CH2 
COOH  | 

COOH  COOH 

This  method  of  synthesis  makes  clear  its  structure. 

Malonic  acid  is  a  crystalline  compound  melting  at  132°. 
It  is  found  in  beet  juice.  On  heating  to  140-150°  it  de- 
composes with  the  formation  of  carbon  dioxide  and  acetic 
acid: 

COOH— CH2— COOH  =  CO2  +  CH3— COOH 

This  property  is  common  to  the  dibasic  acids  in  which 
the  two  carboxyl  groups  are  linked  to  one  carbon  atom. 
When  heated  above  their  melting  points  they  lose  one 
molecule  of  carbon  dioxide. 

102.  Malonic  Ester  Synthesis.  —  The  most  important 
derivative  of  malonic  acid  is  its  diethyl  ester.  It  is  a 
liquid  with  a  slight  odor  which  boils  at  195°.  It  is  re- 
markable for  the  peculiar  behavior  of  the  hydrogen  atoms 
of  its  methylene  group.  When  malonic  ester  is  treated 
with  sodium,  hydrogen  is  evolved  and  a  metallic  derivative, 
sodiomalonic  ester,  is  formed  : 

COOC2H6 
CHNa 


Sodiomalonic  ester 


204     Organic  Chemistry  for  Students  of  Medicine 

This  property  of  the  hydrogen  atoms  of  methylene 
groups  being  replaceable  by  metals  is  found  only  in  com- 
pounds in  which  the  methylene  group  is  linked  on  both 
sides  to  strongly  negative  groups.  Other  instances  of  this 
character  will  appear  later  (see  aceto-acetic  acid,  127). 

This  compound  reacts  with  alkyl  iodide  just  as  do  the 
sodium  alcoholates  (24),  the  sodium  being  replaced  by  the 
alkyl  groups : 

COOC2H5  COOC2H5 

I  I 

CHNa       +  ICH3  =  CH— CH3  +  Nal 

COOC2H5  COOC2H5 

Malonic  eater 

The  resulting  alkyl  derivative  on  saponification  yields 
methylmalonic  acid,  which  on  heating  above  its  melting 
point  decomposes  into  propionic  acid. 

COOC2H5  COOH  CH3 

I                +2H2ol                 -CO2  I 
CH-CH3 -*  CH-CH3 >  CH2 

I  I  I 

COOC2H5  COOH  COOH 

By  treating  methylmalonic  ester  with  sodium  the  second 
hydrogen  is  replaced  by  metal  and  this  in  turn  can  be 
substituted  by  methyl,  ethyl,  etc.  groups,  which  on  loss 
of  CO2  yield  dimethyl,  methyl-ethyl,  etc.,  derivatives  of 
acetic  acid,  viz.  isobutyric  and  isovaleric  acids.  The 
malonic  ester  synthesis  is  therefore  a  general  method  for 
preparing  any  of  the  isomeric  monobasic  fatty  acids  as  well 
as  a  great  number  of  homologues  of  malonic  acid. 


The  Dibasic  Acids  205 

Succinic  acid  and  urea  condense  to  barbituric  acid  (139). 
103.   Succinic  Acid.  - 

COOH    This  acid  occurs  in  the  urine  after  ingestion  of 
|  asparagus.     It  is  found  in  amber,  fossilized  wood, 

™*  and  many  plants.  It  is  crystalline  and  melts 
at  182°.  That  this  acid  is  a  homologue  of 
malonic  acid  is  shown  by  its  synthesis  from  ethy- 
COOH  lene  bromide,  through  ethylene  cyanide,  which 
on  hydrolysis  yields  succinic  acid. 

CH2Br     KCN      CH2—  CN  CH2—  COOH 

|          +          -»|  +  4H20->| 

CH2Br     KCN      CH2—  CN  CH2—  COOH 

Ethylene  cyanide 

The  dibasic  acids  can  likewise  be  synthesized  by  the 
malonic  ester  synthesis.  Not  only  does  sodiomalonic 
ester  react  with  alkyl  halides  (102),  but  with  halogen  de- 
rivatives such  as  the  ester  of  chloracetic  acid  : 

COOC2H5  COOC2H5 


CHNa       +C1—  CH2—  COOC2H5  =  CH—  CH2—  COOC2H6 

chlor  ethylacetate 

COOC2H5  COOC2H5 

I 


COOH  |COO|H 


-CO2  I 
CH2     « CH— CH2— COOH 

I  I 

CH2  COOH 

COOH 


206    Organic  Chemistry  for  Students  of  Medicine 

By  the  same  reaction  substituted  succinic  acids  can  be 
obtained.  Thus  by  employing  a-brom  propionic  acid 
methyl  succinic  acid  is  obtained. 

COOR 


CHNa+Br—  CH 

I  I 

COOR  COOC2H5 

COOR 

/CHs 
=  CH—  CH(  +  NaBr->  CH— 

|  \COOC2H6  |  \COOH 

COOR  COOH 

|-C02 
CH3—  CH—  COOH 

CH2—  COOH 

Methyl  succinic 
acid 

104.  Aspartic  Acid,  COOH—  CH2—CHNH2—  COOH.  — 

The  a-amino  derivative  of  succinic  acid  is  one  of  the  prod- 
ucts of  the  hydrolysis  of  all  proteins  except  the  protamines 
(243).  The  carbon  atom  to  which  the  amino  group  is 
attached  is  asymmetric  (30)  and  it  exists  therefore  in  two 
optical  forms.  From  the  proteins  the  levo  form  is  always 
obtained.  Since  it  contains  both  carboxyl  and  amino 
groups  it  forms  salts  with  both  acids  and  bases,  with  the 
latter  two  series  according  to  whether  one  or  both  of  the 
carboxyl  groups  enter  into  salt  formation.  The  acid  salts, 
i.e.  those  having  one  free  carboxyl  group  and  the  amino 
group,  react  neutral  ;  those  in  which  the  carboxyl  groups 


The  Dibasic  Acids  207 

are  both  neutralized  by  a  base  react  alkaline  through  the 
influence  of  the  amino  group. 

The  normal  copper  salt  of  1-aspartic  acid,  C^sC^N  •  Cu 
+  4^H2O,  is  soluble  in  2870  parts  of  water  at  ordinary 
temperature,  and  in  234  parts  of  boiling  water. 

The  diethyl  ester  of  aspartic  acid  boils  without  decom- 
position under  11  mm.  pressure  at  126.5°.  The  ethyl 
esters  of  the  monobasic  amino  acids  are  hydrolyzed  by  a 
few  hours'  boiling  with  water.  Aspartic  ester  is  stable  in 
boiling  water,  but  is  hydrolyzed  by  2  hours'  heating  with 
an  excess  of  barium  hydroxide. 

105.  Asparagine.  — 

CONH2    a-amino  succinamide  is  the  half  amide  of  aspartic 

acid.     It  is  found  in  large  amounts  in  the  juice 

•     2          of  sprouted  seeds  of  the  legumes.     Asparagihe 

CHNH     f°rms  larSe  rhombic  hemihedral  prisms  soluble 

in  47  parts  of  water  at  20°,  and  insoluble  in 

COOH     alcohol.     1-asparagine  has  a  sweet  taste. 

Glutaric  Acid,  COOH— CH2—CH2—CH2— COOH, 
which  occurs  in  the  washings  of  sheep's  wool,  is  the  next 
higher  homologue  of  succinic  acid.  The  acid  itself  is  of 
biological  interest  because  certain  of  its  derivatives  are 
found  in  nature.  Chief  among  these  are  glutamic  acid, 
or  a-amino  glutaric  acid,  and  glutaminey  the  half  amide  of 
glutamic  acid.  It  results  from  the  hydrolysis  of  pro- 
pylene  nitrile,  CN — CH2 — CH2 — CH2 — CN,  and  can  also 
be  prepared  from  sodiomalonic  ester  by  treatment  with 
/3-iodo  propionic  ester,  saponifying  and  heating  the  result- 
ing tricarboxylic  acid  above  its  melting  point  (102). 
It  crystallizes  in  large  prisms  which  melt  at  97.5°  and 


208     Organic  Chemistry  for  Students  of  Medicine 

boil  at  304°.     It  is  easily  soluble  in  water,  alcohol  and 
ether. 

106.  Glutamic  Acid,  COOH— CH2— CH2— CHNH2— 
COOH,  a-amino  glutaric  acid,  is  present  in  many  proteins, 
forming  about  40  %  of  the  total  nitrogen  content  of  the 
wheat   proteins,    gliadin    and   glutenin.     The    naturally 
occurring  form  is  dextrorotatory,  but  its  salts  rotate  the 
plane  of  polarized  light  to  the  left.    Its  diethyl  ester  boils 
under  10  mm.  pressure  at  139-140°.    Glutamic  acid  is  sol- 
uble at  16°  in  100  parts  of  water.     It  forms  salts  with  both 
acids  and  bases  as  does  aspartic  acid  (104).     Of  special 
importance  for  its  isolation  is  the  hydrochloride,  which 
is  very  sparingly  soluble  in   concentrated   hydrochloric 
acid.     On  saturating  its  solutions  with  hydrochloric  acid 
gas  the  hydrochloric  acid  salt  separates  on  cooling  nearly 
quantitatively.     This  property  differentiates  it  from  as- 
partic acid. 

107.  Glutamine,     CONH2— CH2— CH2— CHNH2— 
COOH,  is  found  widely  distributed  in  the  sap  of  plants. 
After  everything  which  is  precipitable  by  lead  has  been 
removed  from  plant  extracts,  glutamine  is  precipitated  by 
mercuric  nitrate.     Certain  other  amino  acids  are  likewise 
precipitated  with  it,  so  that  its  purification  is  not  simple. 
It  is  much  more  soluble  in  water  than  is  asparagine.     It 
seems  highly  probable  that  glutamic  acid  occurs  within  the 
protein  molecule  as  glutamine.     On  hydrolysis  with  acids 
the  amide  group  is  converted  into  ammonia  (90). 

108.  Adipic  Acid,  COOH— (CH2)4— COOH,  is  said  to 
occur  in  beet  juice.     It  is  formed  by  the  action  of  silver 
on  /3-iodio  propionic  acid. 


The  Dibasic  Acids  209 


HOOC— CH2— CH2 


CH2— CH2— COOH 

Ag+Ag 

=  HOOC— (CH2)4— COOH 

It  melts  at  148°.  It  is  of  interest  mainly  because  it  is 
convertible  into  a  ring  structure.  This  will  be  described 
later  (111). 

Pimelic  Acid,  COOH— (CH2)5— COOH,  has  not  been 
found  in  nature.  It  melts  at  103°,  and  is  soluble  in  25 
parts  of  water  at  20°. 

Suberic  Acid,  COOH— (CH2)6— COOH,  melts  at  141°. 
At  15.5°  one  part  of  the  acid  is  soluble  in  600  parts  of 
water. 


CHAPTER   X 
THE   POLYMETHYLENE   COMPOUNDS 

CH2 
109.   Trimethylene,   |       ^>CH2,  is  obtained  by  the  ac- 

CH/ 
tion  of  metallic  sodium  on  trimethylene  bromide : 


CH2Br  CH 

I 
CH2  +  2  Na  = 

CH2Br 

CH2Br 
CH2Br 


This  compound  is  also 
formed  by  the  interaction 
of  ethylene  bromide  on 
sodiomalonic  ester: 


COOC2H5 


Trimethylene  is  isomeric  with  propylene,  CH2  = 
CH — CHs,  but  differs  from  it  in  its  properties.  Both  are 
gases,  but  whereas  propylene  is  easily  oxidized  by  potas- 
sium permanganate,  trimethylene  is  not  attacked  by  this 
reagent.  It  unites  with  bromine  only  very  slowly  to  form 
trimethylene  bromide,  and  more  readily  with  hydriodic 

210 


The  Polymethylene  Compounds  211 

acid  to  form  normal  propyl  iodide.  The  heat  of  combus- 
tion of  trimethylene  is  much  greater  than  that  of  its 
isomer  (83). 

The  slow  reaction  of  trimethylene  with  bromine  indi- 
cates that  the  ring  structure  is  in  equilibrium  with  a  very 
small  amount  of  an  active  dissociation  product,  probably, 

CH 


110.  Tetramethylene  is  not  known  except  in  the  form 
of  certain  derivatives.    When  trimethylene  bromide  reacts 
with  sodiomalonic  ester,  the  dicarboxylic  ester  of  tetra- 
methylene  is  formed : 

CH2Br          COOR          CH2  COOR 

I  I  /    \l 

CH2      H-NasC          =CH2        C 

I  I  \   /I 

CH2Br          COOR          CH2  COOR 

CH2    |COO|H         CH2 

/\/  /\ 

->     CH2C  =  CH2  CH2 

\X\, .          \/ 

CH2    |COQ|H        CH2 

Tetramethylene 

CH2— CH2, 

111.  Pentamethylene,     |  ;>CH2.      This    hy- 

CH2— CH/ 

drocarbon  can  be  obtained  by  the  malonic  ester  synthesis 
when  tetramethylene  bromide  is  employed  with  sodio- 
malonic ester.  It  is  likewise  formed  by  a  series  of  reac- 


212     Organic  Chemistry  for  Students  of  Medicine 


tions  which  are  of  interest,  starting  with  the  calcium  salt 
of  adipic  acid : 


CH2— CH2—  C0[(r I     CH2- 

Calcium  adipate  Ketopentamethylene 

The  structure  of  the  ketone  derivative  of  pentamethyl- 
ene  is  further  shown  by  the  fact  that  it  oxidizes  to  glutaric 


acid : 


CH2—  CH2—  COOH 


CH2—  COOH 

Pentamethylene  itself  is  obtained  by  reducing  its  ketone 
derivative  to  a  secondary  alcohol,  then  replacing  the 
hydroxyl  of  the  alcohol  by  iodine  by  treatment  with  hydri- 
odic  acid,  followed  by  the  replacement  of  the  iodine  by 
hydrogen  : 


C/XX2  -  O.H.2 


2  -  C/XA2 


CH2  — 


CHI    +2H 


O  .H.2 — \j  fi' 


\j  -H-2 

Pentamethylene 


Pentamethylene  is  a  liquid  boiling  at  50°.  It  will  be 
recalled  that  normal  pentane  boils  at  37°.  While  the 
tetramethylene  ring  shows  a  tendency  to  open  and  add 
two  halogen  atoms,  it  does  not  undergo  this  change  as 
readily  as  does  trimethylene.  Pentamethylene,  however, 
is  so  stable  that  it  does  not  react  with  bromine.  It  is 
exceedingly  stable  toward  oxidizing  agents,  as  nitric  acid, 


The  Polymethylene  Compounds  213 

and  shows  none  of  the  tendency  of  unsaturated  compounds 
to  condense  with  sulphuric  acid  (125). 

<C  H2 — C  H2  \ 
>CH2,       is 
CH2— CH/ 

formed  from  the  calcium  salt  of  normal  pimelic  acid  in  a 
manner  entirely  analogous  to  that  described  for  the  for- 
mation of  pentamethylene. 

Hexamethylene  is  stable  toward  oxidizing  agents  such 
as  potassium  permanganate,  and  does  not  form  an  addition 
product  with  bromine.  It  has  an  odor  like  petroleum,  and 
boils  at  69°. 

113.  Heptamethylene, 

/{.;  -H-2 v>  -H-2  v 
XCH2 
CH2  f 

XCH2 
XCH2— CH2/ 

The  ketone  derivative  of  this  hydrocarbon  can  likewise 
be  prepared  in  the  manner  just  described  by  dry  distilla- 
tion of  the  calcium  salt  of  suberic  acid,  COOH — (CH2)6— 
COOH.  And  an  eight-membered  ring  results  from  the 
calcium  salt  of  azeliac  acid,  COOH— (CH2)7— COOH. 

The  stability  of  the  polymethylene  compounds  in- 
creases up  to  pentamethylene.  There  is  little  difference 
in  stability  between  this  and  hexamethylene,  but  ring 
structures  having  seven  and  eight  carbon  atoms  show 
progressive  decrease  in  stability.  The  reason  for  this 
was  suggested  by  Baeyer,  and  was  formulated  in  the 
following  way :  — 


214    Organic  Chemistry  for  Students  of  Medicine 

"  The  four  valences  of  a  carbon  atom  act  parallel  to 
lines  forming  the  corners  of  a  tetrahedron  with  its  cen- 
ter, making  angles  of  109°  28'  with  one  another.  The 
direction  of  the  valences  can  be  altered,  but  any  such 
alteration  produces  a  strain  whose  amount  is  propor- 
tional to  the  angle  through  which  the  valences  are 
diverted." 


The  following  figures  show  the  angle  of  deviation  neces- 
sary for  the  formation  of  the  ring  structure  in  the  several 
polymethylenes  : 

Trimethylene  24°  44' 

Tetramethylene  9°  44' 

Pentamethylene  0°  44' 


The  Polymethylene  Compounds  215 

Hexamethylene  -5°  16' 

Heptamethylene         -9°  33' 
Octamethylene          -12°  51' 

The  strain  is  least  in  the  case  of  pentamethylene  among 
all  the  cyclo  methylene  compounds,  which  corresponds 
with  its  stability. 

In  harmony  with  the  facts  mentioned  in  support  of  the 
validity  of  the  "  strain  theory  "  is  the  observation  that 
heptamethylene  when  heated  with  bromine  in  a  sealed 
tube  changes  to  a  methyl-substituted  hexamethylene  ring. 
These  compounds  are  often  called  cyclopropane,  cyclo- 
butane,  cyclopentane,  etc. 

The  formation  of  a  ring  structure  has  in  itself  but  little 
influence  upon  the  properties  of  the  hydrocarbons. 

114.  Anhydrides  of  the  Dibasic  Acids.  —  Oxalic  and 
malonic  acids  do  not  form  anhydrides.  Succinic  and 
glutaric  acids  readily  lose  the  elements  of  a  molequle  of 
water  from  within  a  single  molecule  of  the  acid,  forming 
cyclic  anhydrides  : 

CH2—  COOH  CH2—  COV 

|  -H20=  |  >0 

CH2—  COOH  CH2—  CO/ 

Succinic  anhydride 

/CH2—  COOH  /CH2—  COV 

CH2  -H20  =  CH2  0 


2  -2    =       2 

XCH2-COOH  XCH2-CO/ 

Glutaric  anhydride 

Molecular  weight  determinations  of  these  anhydrides 
have  shown  that  the  anhydride  formation  does  not  take 
place  between  two  molecules  of  acid.  Simple  solution  of 


Organic  Chemistry  for  Students  of  Medicine 

these  anhydrides  in  water  converts  them  back  into  the 
acids  from  which  they  were  derived. 

The  failure  of  the  two  and  three  carbon  dibasic  acids  to 
form  anhydrides  is  in  harmony  with  the  "  strain  theory  " 
(113). 

115.  Succinimide.  —  When  the  ammonium  salt  of  suc- 
cinic  acid  is  heated  strongly  to  the  distillation  point,  a  mole- 
cule of  ammonia  and  one  of  water  are  split  off  and  a  ring 
structure  containing  the  imide  group  =NH  is  formed  : 

CH2—  COONH4  CH2-C(\ 

!  -NH3  and  H2O  =    |  NH 


CH2—  COONH4  CH2— 

Succinimide  is  a  crystalline  compound  which  melts  at 
125°  and  boils  at  288°.  On  warming  with  barium  hy- 
droxide solution  it  takes  on  one  molecule  of  water,  forming 
the  half  amide  of  succinic  acid  : 

CH2—  CO\  CH2—  COOH 

|  )NH+H20=   | 

CH2—  CO/  CH2—  CO—  NH2 

Glutarimide  is  produced  in  a  similar  manner  from  the 
ammonium  salt  of  glutaric  acid.  These  are  examples  of 
compounds  in  which  nitrogen  takes  part  with  carbon  in 
the  formation  of  cyclic  compounds. 

116.  Pyrrol, 

CH=CH\  is  formed  from  Succinimide  by  distilling 

|  /NH,    the  latter  with  zinc  dust,  which  ab- 

CH—  CH'  stracts  oxygen  : 

CH2—  CO\  CH=CHV 

|  )NH     -2Q    |  )NH 

CH2-CO/  *  CH=CH/ 


The  Polymethylene  Compounds  217 

Pyrrol  does  not  take  up  halogens  directly,  as  would  be 
expected  from  its  possessing  two  double  bonds.  This 
peculiarity  of  certain  cyclic  compounds  differentiates  them 
sharply  from  the  olefines.  Pyrrol  can,  however,  take  up 
two  atoms  of  hydrogen  when  reduced  with  acetic  acid  and 
zinc  dust  (nascent  hydrogen),  and  the  resulting  Pyrroline, 
or  dihydropyrrol,  absorbs  two  atoms  of  bromine  as  do  the 
olefines.  This  peculiar  behavior  has  led  to  the  assumption 
that  instead  of  the  double  bond  between  the  two  pairs  of 
carbon  atoms  one  bond  from  each  of  the  four  is  directed 
toward  the  center  of  the  ring.  This  form  should  be  very 
stable  as  compared  with  the  double  bond.  The  fact  that 
nascent  hydrogen  is  taken  up  by  pyrrol  probably  finds  an 
explanation  in  the  existence  of  a  small  amount  of  the 
formula  containing  the  double  bond  in  dynamic  equilib- 
rium with  the  centric  formula  : 

CH— CH 

CH   "~~ 


H 

\    / 
NH 

Active  modification  Principal  form 

Inactive 

When  two  atoms  of  hydrogen  are  absorbed  the  centric 
formula  is  changed  to  one  containing  a  double  bond,  as  in 
pyrroline  : 

CH—  CH2  H2C—  CH2 

II  +2H= 


\/ 

NH  NH 

Pyrroline  Pyrrolidine 


218     Organic  Chemistry  for  Students  of  Medicine 

Pyrrol  is  a  constituent  of  coal  tar  and  is  a  product  of  the 
distillation  of  bones.  The  latter  is  called  bone  oil  and 
contains  pyridine  (230)  and  various  cyclic  hydrocarbons, 
benzene,  etc.  (166),  pyrrol  and  its  homologues,  together 
with  large  amounts  of  the  nitriles  of  fatty  acids.  When 
agitated  with  dilute  acid  the  basic  compounds  form  salts 
which  are  soluble  in  water  and  are  removed.  The  nitriles 
are  saponified  by  boiling  with  alkali  and  the  oil  which 
remains  is  distilled.  The  fraction  which  distills  between 
115°  and  130°  contains  the  pyrrol.  The  hydrogen  of  the 
imino  group  is  replaceable  by  metals,  alkyl,  acetyl,  etc., 
and  when  warmed  with  potassium  hydroxide  the  solid 
compound  potassium  pyrrol,  QH^NK,  is  formed.  This  is 
filtered  off  and  decomposed  by  water,  which  regenerates 
pyrrol  :  CH=CH\  CH=CHX 

|  ;NK  +  HOH=  |          )NH 

/  =/ 


Pyrrol  is  a  colorless  liquid  with  an  odor  similar  to 
that  of  chloroform.  It  boils  at  131°,  and  is  but 
slightly  soluble  in  water.  It  dissolves  readily  in  al- 
cohol and  ether.  Potassium  dissolves  in  pyrrol  with 
the  evolution  of  hydrogen,  forming  potassium  pyrrol, 
yet  pyrrol  has  a  feebly,  basic  character.  Pyrrol  gives 
a  bright  red  color  with  a  pine  shaving  moistened  with 
hydrochloric  acid. 

Derivatives  of  Pyrrol.  —  While  pyrrol  itself  is  a  poison- 
ous substance  and  does  not  have  a  biological  role,  several 
of  its  derivatives  are  of  great  importance  as  constituents 
of  the  protein  molecule,  of  chlorophyll,  the  green  pigment 
of  plants,  of  hsemin  and  hsematoporphyrin,  both  of  which 


The  Polymethylene  Compounds  219 

are  derivatives  of  hsemoglobin,  the  respiratory  pigment  of 
the  blood.  Pyrrol  derivatives  are  present  in  nicotine,  an 
alkaloid  contained  in  tobacco,  and  in  the  alkaloids  of  the 
tropine  group,  e.g.  atropine,  cocaine,  etc.,  and  in  the  bile 
pigments.  The  structure  of  the  pyrrol  derivatives  is  indi- 
cated thus  : 


«'HC    CH« 

V 

NH 

The  pyrrol  derivatives  important  from  the  biological 
standpoint  are  the  following  : 

CH3—  C—  C—  C2H6  CHg—  C—  C—  C2H5 


CH  HC    C-CH3 


NH  NH 

Isohsemopyrrpl  Kryptopyrrol 

/3-ethyI,  a'-/3'-dimethyl  pyrrol  a-methyl-/3-ethyl-/3'-methyl  pyrrol 

CH3— C—  C— C2H5      CH3— C— C— CH2— CH2— COOH 

II      II  II      II 

CH3— C     C— CH3       CH3— C    CH 

\/  \/ 

NH  NH 

Phyllopyrrol  Isophonopyrrol  carboxylic  acid 

a-methyl-/3-ethyl-a'-/3'-dimethyl  /3-propionic  acid-a',  /3'-dimethyl  pyrrol 

pyrrol 

All  four  of  these  are  derived  from  hcematin,  a  substance 
containing  iron  which  is  present  in  the  blood  in  combina- 
tion with  globin,  a  protein.  The  entire  complex  is  called 
hsemoglobin.  This  has  the  power  of  combining  with 
oxygen  in  loose  combination  and  thus  serves  to  transport 
oxygen  throughout  the  body. 


220     Organic  Chemistry  for  Students  of  Medicine 


Haamin,  CagHj^N^FeCl,  crystallizes  out  when  defibrin- 
ated  blood  is  dropped  into  a  large  volume  of  glacial 
acetic  acid  containing  some  sodium  chloride,  the  solution 
being  heated  to  95°.  This  treatment  separates  the 
hcematin  from  the  haemoglobin,  and  the  compound  hsemin 
which  crystallizes  out  is  the  hydrochloride  of  hsematin. 
It  forms  minute  bluish  black  crystals  with  a  metallic 
luster.  It  is  insoluble  in  water,  alcohol,  or  ether,  but 
dissolves  in  chloroform  containing  quinine  or  pyridine. 
From  such  a  solution  it  crystallizes  out  when  alcohol  con- 
taining sufficient  hydrochloric  or  acetic  acid  to  neutralize 
the  base  (quinine  or  pyridine)  is  added. 

Hsemin  contains  two  carboxyl  groups.  It  combines 
with  two  molecules  of  hydrobromic  acid.  The  iron  becomes 
loosened  in  this  reaction,  and  some  further  unknown  change 
takes  place.  The  dibrom  compound  when  hydrolyzed 
loses  its  bromine,  the  latter  being  replaced  by  two  hydroxyls. 
The  resulting  compound,  known  as  hsematoporphyrin,  is  a 
dihydroxy-dibasic  acid  :  QH 

/OH 
C3iH34N4<COOH 

XCOOH 

This  when  heated  with  methyl  alcoholic  potassium 
hydroxide  in  pyridine  solution  undergoes  reduction  and 
loses  two  molecules  of  water: 

C33H3806N4  +  H2  =  C33H3604N4  +  2H2O 

The  product  thus  obtained  is  called  hsemoporphyrin. 
It  is  a  dibasic  acid.  On  heating  hasmoporphyrin  with  soda 
lime  (a  mixture  of  CaO  and  Na2O)  the  two  carboxyl  groups 


The  Polymethylene  Compounds  221 

are  destroyed,  CO2  being  split  off,  and  a  new  compound, 
oetioporphyrin,  is  formed.  The  following  formulae  for  the 
last-named  derivatives  have  been  proposed  by  Willstatter  : 

HC^CH 
CH3—  C—  CH 


C2H5—  C—  C  C—  CH 

xC—  —  C  - 


NH      HN 

CH3—  C=C  C—  C—  CH3 

XCH3  | 

CH3 

^Etioporphyrin,  CsiHasNi 


CH3—  C—  CH 


CH3—  C= 


C 


C2H5—  C—  C/ 

%€ 

HOOC—  CH2—  CH2—  C=C/  yC=C—  CH2-CH2-COOH 

NH    HN 


H3 

Hsemoporphyrin, 

^Etioporphyrin  is,  according  to  the  researches  of  Will- 
statter and  his  pupils,  the  mother  substance  from  which 
both  chlorophyll  and  hsematin  are  derived.  In  both 
therefore  the  molecules  consist  of  four  substituted  pyrrol 
groups.  They  assume  that  the  iron  in  haematin  is  united 
with  nitrogen. 

In  chlorophyll  the  condensed  pyrrol  nucleus  possesses 


222     Organic  Chemistry  for  Students  of  Medicine 

two  carboxyl  groups  which  are  united  with  two  alco- 
hols, methyl  alcohol  and  phytol,  a  secondary  alcohol  with 
the  formula  C2oH39OH,  to  form  an  ester.  Instead  of 
iron,  chlorophyll  contains  magnesium  linked  to  nitrogen. 
A  number  of  decomposition  products  of  both  hsematin 
and  chlorophyll  have  been  described  and  carefully 
studied  with  a  view  to  elucidating  their  chemical  na- 
ture, but  their  description  would  be  beyond  the  scope 
of  this  book.  The  essential  fact  to  be  borne  in  mind  is 
the  close  chemical  relationship  between  these  plant  and 
animal  pigments. 

It  should  be  pointed  out  as  an  interesting  biological  fact 
that  carefully  conducted  feeding  experiments  with  labora- 
tory animals  have  shown  that  neither  chlorophyll  nor 
hsematin  is  an  essential  constituent  of  the  diet.  The  ani- 
mal body  is  able  to  construct  the  red  respiratory  pig- 
ment from  certain  of  the  amino  acids  yielded  by  the 
proteins  of  the  food.  Probably  those  containing  the 
pyrrol  ring  are  of  particular  importance  for  this  purpose. 

The  bile  acids,  bilirubin  and  biliverdin,  are  derived  from 
disintegrated  red  corpuscles  and  are  derivatives  of  con- 
densed pyrrol  nuclei  which  have  their  origin  in  the  hsema- 
tin complex  of  the  hsemoglobin. 

117.  Pyrrolidine  is  of  great  biological  interest  since 
CH2 — CH2  its  derivatives,  proline  (a-pyrrolidine 

|  NNH  carboxylic  acid)  and  oxyproline 

CKk — CH2  (a-oxypyrrolidine  carboxylic  acid), 

occur  among  the  amino  acids  which  result  from  the  hy- 
drolysis of  proteins. 

In  addition  to  the  method   described   for  preparing 


The  Polymethylene  Compounds  223 

pyrrolidine  (116),  another  which  confirms  its  structure  is 
its  formation  from  ethylene  cyanide.  When  treated  with 
sodium  and  alcohol,  the  nascent  hydrogen  formed  induces 
the  following  series  of  changes  : 

CH2—  CN  CH2—  CH2—  NH2 

|  +8H=   | 

CH2—  CN  CH2—  CH2—  NH2 

Ethylene  cyanide  Tetramethylene-diamine 

CH2  —  CH2v 

=    |  >NH+NH3 

CH2—  CH/ 

Pyrrolidine 

Pyrrolidine  boils  at  87°. 

118.    Proline,  a-pyrrolidine  carboxylic  acid, 
H2C—  CH2 

I        I 
H2C     CH—  COOH 


NH  '•- 

is  a  product  of  the  hydrolysis  of  many  proteins  of  both 
animal  and  plant  origin.  1-proline  is  the  form  occurring 
in  nature.  Its  structure  is  made  evident  by  its  synthesis 
from  a-amino  /3-oxyvalerianic  acid.  This  on  heating  loses 
a  molecule  of  water  and  forms  proline  : 

CH2—  CH2  CH2—  CH2 


CH2  CH—  COOH  .  °*   CH2  CH—  COOH+H20 

I    I  \/ 

OH  NH2  NH 

Proline  is  easily  soluble  in  water.  It  is  the  only  one  of 
the  naturally  occurring  amino  acids  which  is  readily 
soluble  in  absolute  alcohol.  The  blue  copper  salt  is  like- 


224     Organic  Chemistry  for  Students  of  Medicine 

wise  soluble  in  alcohol,  and  this  salt  is  made  use  of  in  the 
purification.  Racemic  proline,  the  mixture  of  equal  parts 
of  the  two  optical  forms,  forms  a  copper  salt  which  is 
violet  when  dry  but  absorbs  moisture  from  the  air  and 
becomes  blue  again.  Proline  forms  a  salt  with  picric  acid 
(184)  which  is  useful  in  its  identification.  Among  the 
proteins  gelatin  yields  the  largest  amount  of  this  amino 
acid. 

119.  Oxy-Proline,  a-oxy-pyrrolidine  carboxylic  acid, 

HO— CH— CH2 

I         I 
CH2   CH— COOH 

V 

NH 

occurs  in  gelatin.  It  decomposes  at  270°  with  foaming. 
The  vapors  evolved  give  the  reactions  of  pyrrol  (116). 

120.  Pyrrolidone  Carboxylic  Acid.  —  Of  theoretical  in- 
terest is  the  property  of  glutamic  acid  (106)  of  separating 
a  molecule  of  water  when  heated  to  185-190°  with  the 
formation  of  a  ketone  derivative  of  proline : 

OOH  CH2  — CH— COOH 

-H2O  ' 


CH2— CO 

a-pyrrolidone  carboxylic  acid 

CH2 — CH2 

+  4H    I          I 

>  CH2     CH— COOH 


NH 


CHAPTER   XI 
HYDROXY    AND    KETONE    ACIDS 

Hydroxy  Dibasic  Acids 

121.   Tartronic  Acid.  —  The  simplest  member   of   the 

COOH 

I 
series  of  dibasic  hydroxy  acids  is  tartronic  acid,  CHOH 

COOH 

This  acid  does  not  occur  in  nature.     It  is  formed  from 
malonic  acid  by  the  following  reactions  : 

COOH  COOH  COOH 

* 


COOH  COOH  COOH 

Tartronic  acid  melts  at  187°  with  the  loss  of  carbon 

[COOjH      _co,      CH2OH 
CHOH  *      COOH 

COOH 

The  glycolic  acid  formed  at  this  temperature  at  once 
reacts  with  a  second  molecule  to  form  an  ester  called 
glycolide. 

Q  225 


226     Organic  Chemistry  for  Students  of  Medicine 


CH20|H  _  HO^OC      CH2-OOC 


CO|OH       H|OH2C 

122.  Malic  Acid,  hydroxysuccinic  acid,  is  present  in 
COOH  various  unripe  fruits,  as  apples,  pears,  etc. 
It  is  best  prepared  from  unripe  mountain 
ash  berries  or  from  rhubarb  stalks.  Its 
structure  is  indicated  by  its  conversion  into 
chlorsuccinic  acid  by  treatment  with  phos- 
COOH  phorus  pentachloride,  and  by  the  fact  that 
the  alcohol  group  in  succinic  ester  reacts  with  acetyl 
chloride,  forming  an  acetyl  derivative  : 

COOC2H5  COOC2H5 

I  I 

CHOH       +C10C-CH3     CHOOC-CHa 


CH2 
COOC2H5 

CH2 
COOC2H, 

On  boiling  the  juice  of  rhubarb  or  of  mountain  ash 
berries  with  milk  of  lime,  calcium  malate  is  precipitated, 
since  it  is  relatively  insoluble.  The  salt  is  washed,  dried, 
and  weighed,  and  is  then  treated  with  the  calculated 
amount  of  sulphuric  acid.  Insoluble  calcium  sulphate 
separates  out.  The  solution  containing  the  malic  acid  is 
evaporated  to  the  point  of  crystallization. 

Malic  acid  is  readily  soluble  in  water,  alcohol,  and 
ether.  The  calcium  salt  is  precipitated  from  dilute  water 
solutions  by  the  addition  of  alcohol.  Like  normal  cal- 


Hydroxy  and  Ketone  Acids  227 

cium  butyrate  (70)  it  is  more  soluble  in  cold  water  than 
in  hot  and  is  precipitated  from  concentrated  solutions 
on  boiling. 

Since  malic  acid  contains  an  asymmetric  carbon  atom 
it  exists  in  two  isomeric  forms  which  differ  only  with 
respect  to  their  behavior  toward  polarized  light.  (See 
amyl  alcohol.)  The  natural  form  is  1-malic  acid.  When 
malic  acid  is  heated  to  180°,  it  loses  a  molecule  of  water 
and  forms  maleic  and  fumaric  acids.  These  possess  a 
double  bond,  COOH— CH=CH— COOH.  They  will  be 
treated  later  (133). 

123.   Tartaric  Acids,  dihydroxy  succinic  acid. 

COOH 
CHOH 
CHOH 

COOH 

There  are  four  acids  having  this  composition.  They 
all  react  with  PC15  to  give  dichlor  succinic  acid,  and  when 
reduced  by  heating  with  hydriodic  acid  they  yield  in 
turn  malic  and  succinic  acids. 

CHOH— COOH       CHOH— COOH 

+  2H  |  +H20 

CHOH— COOH       CH2— COOH 

CH2— COOH 

+  2H  I 

CH2— COOH 


228    Organic  Chemistry  for  Students  of  Medicine 

Their  differences  are  the  result  of  the  presence  of  two 
asymmetric  carbon  atoms  in  their  molecules  which  makes 
possible  enantiomorphous  isomerism.  (See  lactic  acids.) 
With  the  presence  of  two  asymmetric  carbon  atoms  in  a 
molecule  four  modifications  of  the  compound  must  exist, 
viz. :  a  right-rotating  and  a  left-rotating  form,  an  inactive 
form  composed  like  inactive  amyl  alcohol  or  inactive  lactic 
acid  of  equal  molecules  of  the  d-  and  1-  forms,  and  a  fourth 
modification,  mesotartaric  acid,  likewise  inactive,  in  which 
the  configuration  of  one  asymemtric  carbon  atom  is  the 
mirror  image  of  the  other  one  in  the  same  molecule,  i.e. 
the  rotatory  power  is  internally  compensated.  It  is 
impossible  to  establish  in  the  case  of  any  two  configura- 
tion formulae,  e.g.  the  lactic  acids,  which  mode  of  arrange- 
ment actually  represents  the  d-  or  the  1-  form,  but  if  we 
make  an  arbitrary  assumption  in  the  case  of  one  configu- 
ration, as  for  example  that  any  one  grouping  represents 
levorotation,  its  mirror  image  must  represent  the  oppo- 
site or  dextrorotation : 


H-i 


—OH          HO— C— H 

I  I 

COOH  COOH 

Levorotatory  Dextrorotatory 

arrangement  arrrangement 

When  one  of  these  groupings  is  inverted  so  as  to  be  united 
with  the  other  to  form  one  molecule,  the  entire  complex 
must  be  levorotatory  as  I,  and  its  image  II  will  be  dextro- 
rotatory. In  III  the  two  halves  of  the  molecule  will 
mutually  neutralize  the  effect  of  each  on  the  plane  of 


Hydroxy  and  Ketone  Acids 


229 


polarized  light,  and  an  inactive  compound  results.  This 
form  is  called  mesotartaric  acid  to  differentiate  it  from  the 
racemic  form,  which  consists  of  both  the  d-  and  1-  acids 
in  equal  amounts.  Mesotartaric  acid  cannot  be  separated 
into  d-  and  1-tartaric  acids  as  can  the  racemic  tartaric 
acid. 

COOH        COOH         COOH 


HO— C— H 
H— C— OH 

COOH 
i 

COOH 


H— C— OH 
HO— C— H 

COOH 

ii 

COOH 


H 


I    IH 

|__fOH 

H   |      |OH 
HO  f  |  H 

COOH 
i 

COOH 

ii 

HO— C— H 
HO— C— H 

COOH 

in 

COOH 

HO| |  H 
HOf |  H 

COOH 
in 


Racemic  acid  is  actually  a  compound  of  one  molecule 
of  d-  and  one  of  1-tartaric  acids  and  not  simply  a  mixture 
of  the  two  kinds  of  molecules.  It  has  a  different  crys- 
talline form  from  the  two  active  acids,  and  the  crystals 
carry  water  of  crystallization.  The  racemic  acid  crys- 
tals are  much  less  soluble  in  water  than  are  the  active 
acids,  and  have  a  higher  melting  point.  The  union  is 
however  a  feeble  one,  and  in  solution  it  exists  as  separate 
molecules  of  the  optically  active  acids.  This  is  indicated 
by  the  fact  that  the  molecular  weight  as  shown  by  the 


230     Organic  Chemistry  for  Students  of  Medicine 

freezing  point  and  boiling  point  methods  corresponds 
to  the  formula  C4H6O6.  The  esters  of  tartaric  acids 
are  volatile,  and  their  vapor  densities  correspond  to  the 
single  instead  .of  to  double  molecules.  Crystals  of  ra- 
cemic  acid  have  the  composition  2  C4H6O6  +  2  H20. 
d-  and  1-tartaric  acids  crystallize  without  water  of  crys- 
tallization. 

Dextro-  and  levo-tartaric  acids  melt  at  170°.  100  parts 
of  water  at  20°  C.  dissolve  139.44  parts,  and  at  100° 
343.35  parts  of  either  the  d-  or  1-  acids.  They  are  much 
less  soluble  in  alcohol  and  insoluble  in  ether.  Tartaric 
acid  when  strongly  heated  with  a  dehydrating  agent  such 
as  potassium  bisulphate  loses  water  and  carbon  dioxide 
and  there  distills  over  a  ketone  acid,  pyruvic  acid.  This 
acid  is  likewise  known  as  pyroracemic  add  and  as  methyl 
glyoxylic  acid  (67). 


CH3 

CHOH     -CO2  and  H2O      I 
|  >    CO 

CHOH  I 

|  COOH 

rr^OTI  Pyruvic  acid 

Methyl  glyoxylic  acid 

Pyruvic  acid  has  great  biological  interest.  It  will  be 
further  considered  in  connection  with  carbohydrate 
metabolism  and  the  synthesis  of  fats.  It  is  probable  that 
the  first  step  in  the  decomposition  is  the  loss  of  carbon 
dioxide  and  the  formation  of  glyceric  acid  which  then 
loses  a  molecule  of  water.  Glyceric  acid  itself  when  heated 
is  converted  into  pyruvic  acid. 


Hydroxy  and  Ketone  Acids  231 

CH2OH 


CHOH  ~H2°>  CO 

I  I. 

COOH      cogn 

The  acid  potassium  salt  of  d-tartaric  acid  crystallizes 
out  of  wine  as  alcohol  accumulates  during  fermentation. 
The  crude  salt  is  known  as  argol  and  contains  some  cal- 
cium tartrate  and  coloring  matters.  The  acid  potassium 
salt  is  dissolved  in  hot  water,  leaving  the  calcium  salt 
behind,  and  after  treatment  with  animal  charcoal  to  re- 
move coloring  matters  the  solution  is  allowed  to  cool 
COOK  anc^  crystallize.  This  salt  is  then  known 

as  cream  of  tartar.  It  is  very  sparingly 
(CHOH)2  soluble  in  water  and  still  less  so  in  alcohol. 

It  is  extensively  used  in  baking  powders. 

Here  it  is  mixed  with  sodium  bicarbonate, 
with  which  it  reacts  when  dissolved  to  form  sodium 
potassium  tartrate  or  Rochelle  salt: 

COOK  COOK 

I  I 

(CHOH)2  +  HNaCO3  =  (CHOH)2  +  H20  +  CCfe 

COOH  COONa 

Rochelle  salt 

The  carbon  dioxide  being  generated  throughout  the  dough 
causes  it  to  rise  into  a  spongy  condition.  Baking  powders 
are  therefore  a  substitute  for  yeast. 

Dipotassium  tartrate,  C4H4O6K2,  is  readily  soluble  in 
water.     Acid    potassium    tartrate    dissolves     antimony 


232     Organic  Chemistry  for  Students  of  Medicine 

oxide,   SbO,   to   form  potassium   antimonyl    tartrate   or 
tartar  emetic :  COOK 

(CHOH)2 

I 
COOSbO 

Racemic  acid  and  mesotartaric  acid  are  both  formed 
from  d-tartaric  acid  by  boiling  with  sodium  hydroxide. 
This  is  explained  by  the  assumption  that  water  is  alter- 
nately separated  and  added. 

i  COOH  COOH 

Mi  I 

H--C-i-OH  -2H2O  — C- 


HO-;-C--H 

i  i ; 

=  COOH 


COOH 


COOH 


H      HO— C— H      OH 

or  or 

HO      H— C— OH      H 


COOH 


COOH 

COOH 

i 

COOH 

i 

HO—  C—  H 

i 

H—  C—  OH 

HO—  C—  H 

i 

HO—  C—  H 

i 

HO—  ( 

>-  H 

H—  C—  OH 

i 

COOH 

Mesotartaric  acid 

COOH 

d-tartaric  acid 

COOH 

l-tartaric  acid 

Hydroxy  and  Ketone  Acids  233 

According  to  the  law  of  chance,  if  water  is  split  off  from 
a  compound  and  added  on  again  in  the  way  described, 
an  OH  group  will  take  the  place  of  H,  just  as  frequently 
as  it  will  replace  the  separated  OH.  Thus  on  repeating 
the  separation  and  addition  of  water  a  sufficient  number 
of  times  a  state  of  equilibrium  will  be  established  in  which 
all  possible  arrangements  of  H  and  OH  groups  will  exist 
in  the  solution.  Such  a  conception  helps  to  make  clear 
the  process  of  racemization  and  likewise  the  transforma- 
tion of  certain  sugars  into  others. 


SEPARATION  OF  RACEMIC  SUBSTANCES  INTO  THEIR 
OPTICALLY   ACTIVE   CONSTITUENTS 

Optically  active  isomers  show  no  differences  in  their 
solubility,  melting  point,  boiling  point,  or  amount  of 
water  of  crystallization.  They  differ  only  with  respect 
to  their  effect  in  twisting  the  ray  of  polarized  light.  Ordi- 
nary methods  of  separating  mixtures  depend  on  differ- 
ences of  physical  or  chemical  properties,  so  that  for  the 
separation  of  optical  isomers  special  procedures  had  to 
be  devised.  Three  general  methods  for  accomplishing 
such  separations  are  known,  and  all  of  these  were  dis- 
covered by  the  brilliant  French  chemist,  Pasteur. 

The  first  of  these  depends  upon  the  property  possessed 
by  sodium  ammonium  racemate,  when  allowed  to  crys- 
tallize at  temperatures  below  28°,  of  depositing  side  by 
side  the  sodium  ammonium  salt  of  dextro-  and  of  levo- 
tartaric  acids.  These  crystals  possess  hemihedral  faces, 
and  are,  like  mirror  images,  not  superimposable.  They 


234     Organic  Chemistry  for  Students  of  Medicine 

can  be  recognized  by  their  appearance  and  separated  by 
picking  out  the  two  kinds  of  crystals  by  hand.  On  pre- 
paring the  free  acids  from  these  two  kinds  of  crystals  and 
dissolving  each  kind  separately  they  are  found  to  have 
opposite  optical  properties.  On  mixing  the  two  solutions 
racemic  acid  is  re-formed. 

The  second  method  depends  upon  combining  the  d- 
and  1-  forms  of  acids  with  an  optically  active  base.  The 
resulting  salt  molecules  are  no  longer  alike  in  their  con- 
figuration and  therefore  show  different  physical  proper- 
ties. Such  salts  can  be  separated  by  fractional  crystal- 
lization. The  natural  bases  quinine,  einchonine,  brucine, 
and  others  are  optically  active  and  are  useful  in  such 
separations  of  racemic  mixtures  of  acids.  When  the 
racemic  mixture  to  be  separated  is  a  base  an  optically 
active  acid  must  be  selected  (73). 

The  third  method  devised  by  Pasteur  for  obtaining 
an  active  compound  from  a  racemic  mixture  depends 
upon  the  fact  that  but  one  of  the  two  forms  of  the 
enantiomorphous  isomers  has  an  appreciable  biological 
value.  The  proteins  of  which  the  animal  and  plant 
tissues  are  made  up  are  composed  of  optically  active 
amino  acids,  and  only  one  optical  form  of  each  occurs  in 
nature.  The  sugars  are  likewise  optically  active  sub- 
stances. When  a  living  organism  is  present  in  a  racemic 
mixture  of  some  compound  which  it  is  able  to  use  as  a 
source  of  energy,  it  can  in  general  use  one  optical  form 
much  better  than  the  other,  and  not  infrequently  one  of 
such  isomers  is  without  value  as  a  nutrient.  Pasteur 
found  that  the  mold  Penicillium  glaucum  could  make 


Hydroxy  and  Ketone  Acids  235 

use  of  the  ammonium  salt  of  d-tartaric  acid  but  not  the 
1-  form.  (See  lactic  acid.)  Obviously  this  method  is 
available  only  for  obtaining  the  isomer  which  does  not 
occur  in  nature. 

Trihydroxy  Glutaric  Acids,  COOH— CH2OH— CH2OH 
— CH2OH— COOH.  —  There  are  four  possible  isomers 
having  this  structure.  They  result  from  the  oxidation 
of  the  sugars  and  will  be  treated  more  in  detail  later  (152). 

Tetrahydroxy  Dibasic  Acids,  COOH— (CH2OH)4 
COOH,  likewise  are  important  oxidation  products  of  the 
sugars.  The  most  important  are  saccharic  acid,  mucic 
acid,  and  isosaccharic  acids. 

124.  Oxybutyric  Acid  and  Its  Related  Compounds.  — 
The  condensation  of  two  molecules  of  acetaldehyde  to 
form  0-oxybutyric  aldehyde  or  "  aldol  "  has  been  de- 
scribed (32).  Like  other  aldehydes  this  is  oxidizable 
to  an  acid  of  the  same  number  of  carbon  atoms,  /3-oxy- 
butyric  acid : 

CH3— CHOH— CH2— CHO 

±O  CH3— CHOH— CH2— COOH 

This  acid  has  one  asymmetric  carbon  atom  and  so  exists 
in  three  stereoisomeric  forms,  dextro,  levo,  and  inactive, 
of  which  the  levorotatory  form  is  of  the  greatest  physio- 
logical interest  since  it  occurs '  in  the  urine  in  diabetes, 
sometimes  in  surprising  quantities,  more  than  a  hundred 
and  fifty  grams  a  day  having  been  observed. 

l-/3-oxybutyric  acid  closely  resembles  lactic  acid  in  its 
behavior.  It  is  an  odorless  and  colorless  sirup,  non- 


236     Organic  Chemistry  for  Students  of  Medicine 

volatile  with  steam,  and  can  be  obtained  in  the  crystal- 
line form,  but  the  crystals  are  unstable.  It  is  readily 
soluble  in  water,  alcohol,  ether,  and  acetic  ether,  but 
insoluble  in  benzene  and  petroleum  ether.  Its  salts  are 
all  soluble  in  water,  and  difficultly  soluble  in  alcohol,  and 
are  precipitated  from  alcohol  by  the  addition  of  ether. 
The  silver  salt  is  of  use  in  its  detection.  It  consists  of 
fine  white  needles. 

On  heating  with  water  or  dilute  sulphuric  acid  /3-oxy- 
butyric  acid  is  converted  into  crotonic  acid  : 

CH3  CH3 

I  I 

CHOH  CH 

I  -H20  =      || 
CH2  CH 

I  I 

COOH  COOH 

/3-oxybutyric  Crotonic 

acid  acid 

On  oxidation  with  chromic  acid  it  yields  the  ketone  acid, 
aceto-acetic  acid,  which  readily  breaks  down  into  acetone 
and  carbon  dioxide. 


CHOH    ^    CO     _CQ,    CO 
CH2  CH2 


+ 

COOH  COOH 

Aceto-acetic  Acetone 

acid 

125.  v-Hydroxy  Acids,  R-CHOH—  CH2-CH2-COOH, 
show  a  peculiar  tendency  to  lose  water  with  the  formation 


Hydroxy  and  Ketone  Acids  237 

of  internal  esters  called  lactones.  This  tendency  is  so 
pronounced  that  many  acids  of  this  type  are  not  known  in 
the  free  state,  but  only  as  salts,  esters,  etc.  On  being  set 
free  they  at  once  pass  into  the  cyclic  structure.  Alkalies 
convert  lactones  back  into  the  salts  of  the  7-hydroxy 
acids.  The  same  conversion  is  in  part  effected  by  boiling 
with  water. 

R— CH— CH2— CH2— COOH 
|                               -H20 
OH  *R  — CH— CH2— CH2— CO 

i  i 

O 


Lactone 

126.  'y-Amino  Acids  show  the  same  tendency  to  lose 
water  and  form  cyclic  compounds.     These  are  known  as 
lactams : 

R— CH— CH2— CH2— COOH 

NH2  ^SR— CH— CH2— CH2— CO 

I NH- 1 

Lactam 

127.  Aceto-acetic      Acid,      CH3— CO— CH2— COOH, 

possesses  great  physiological  interest  since  it  occurs  in 
the  blood  and  urine  in  diabetes,  where  it  results  from  the 
oxidation  of  /3-oxybutyric  acid.  It  is  a  very  unstable, 
strongly  acid  sirup  which  absorbs  moisture  readily  from 
the  air.  On  warming  it  decomposes  into  acetone  and 
carbon  dioxide  as  illustrated  above.  In  the  tissues  /S- 
oxybutyric  acid  results  from  the  oxidation  of  fat  and  in 
small  amount  from  protein  decomposition.  This  acid  is 
particularly  difficult  for  the  diabetic  to  oxidize,  although 


238     Organic  Chemistry  for  Students  of  Medicine 

the  normal  organism  is  able  to  accomplish  it.  /3-oxy- 
butyric  acid  is  partly  oxidized  to  aceto-acetic  acid  in  the 
blood  and  the  decomposition  of  the  latter  acid  into  acetone 
and  carbon  dioxide  takes  place  spontaneously,  so  that  in 
the  severe  diabetic  blood  there  are  always  found  the  three 
compounds,  £-oxybutyric  and  aceto-acetic  acids  and 
acetone,  together. 

A  certain  peculiarity  in  the  isomerism  displayed  by 
aceto-acetic  acid,  together  with  the  great  importance  of 
its  ester  in  synthesis,  make  it  desirable  to  describe  the 
behavior  of  the  latter  in  some  detail. 

Aceto-acetic  Ester  is  formed  by  the  reaction  of  ethyl 
acetate  with  sodium  ethylate.  There  are  three  stages  to 
the  reaction  :  the  formation  of  an  addition  product  be- 
tween ethyl  acetate  and  sodium  ethylate  : 

/£>  /OXa 

(1)  CHa—  C--O—  QH5  +  NaOC2H5=  CH3—  C^_OC2H5 

\OC2H5 

This  then  reacts  with  a  second  molecule  of  ethyl 
acetate  to  form  the  sodium  compound  of  aceto-acetic 
ester  : 

/OXa        H\ 

(2)  CHs—  C^OQ>H5+H-^C—  COOC2H5 

H/ 
OXa 

=CH—  COOC2H5  +  2  C2H5OH 


The  ethyl  aceto-acetate  is  formed  on  treating  the  sodium 
compound  with  an  acid.  This  is  known  as  Claisen's 
synthesis  : 


Hydroxy  and  Ketone  Acids  239 

OXa 

(3)  CH3— C=CH— COOC2H5  +  CH3— COOH 

=  CH3— CO— CH2— COOC2H5  +  CH3— COOXa 

The  sodium  derivative,  as  will  appear  later,  may  have 
either  of  the  two  following  structures : 

OXa  Xa 

CHs— C=CH— COOC2H5,  or  CH,— CO— CH— COOC2H5 

Aceto-acetic  ester  undergoes  decomposition  in  two  ways 
according  to  the  conditions  to  which  it  is  subjected. 
Dilute  alkalies  or  acids  on  warming  decompose  it  into  a 
ketone,  alcohol,  and  carbon  dioxide.  This  is  known  as 
the  ketone  decomposition  (a).  \Yhen  it  is  decomposed 
by  a  strong  solution  of  alcoholic  potassium  hydroxide 
the  ester  suffers  acid  decomposition  (b). 

(a)  CH3— CO— CH2—  COOJC2H5 
H          JOH 

/"iTT  f~*t~\       /^TT       i     (~^(~\       i     /"*  TT  /"YtT 

=  1^x13 — LU — Lri^  T  v-v>2  T-  L2xi5Ujl 

(6)  CHa— COJ— CH2— COO:— C2H5 

HOJH  H;OH 

=  CH3— COOH  H-  CHs— COOH  +  C2H5OH 

The  great  importance  of  aceto-acetic  acid  in  synthesis 
lies  in  the  fact  that  the  sodium  in  sodio-aceto-acetic  ester 
can  be  substituted  by  various  radicals,  after  which  the 
types  of  decomposition  described  above  yield  ketones  or 
acids. 


240     Organic  Chemistry  for  Students  of  Medicine 

Thus  when  sodio-aceto-acetic  ester  reacts  with  n-octyl 
iodide,  the  octyl  group  replaces  the  sodium.  On  acid 
decomposition  this  compound  yields  capric  acid, 


CH3—  CO—  CHNa 

|  +  ICH2—  (CH2)6—  CH3 

COOC2H5  "-o^1  iodide 

=  CH3—  CO—  CH—  C8H17 

|  +  Nal 

COOC2H6 

i 

OH!     H 
CH3—  CO—  |CH—  C8H17 


HOH 
=  CH3—  COOH  +CH3—  (CH2)8—  COOH  +C2H5OH 

Acetic  acid  Capric  acid  Alcohol 

The  same  compound  when  subjected  to  the   ketone 
decomposition  yields  methyl-nonyl-ketone  : 

CH3—  CO—  CH—  C8H17 


=  CH3—  CO—  C9H19+C02+C2H5OH 

Methyl-nonyl-ketone 

Numerous  higher  acids  and  ketones  have  been  readily 
prepared  by  this  reaction. 


Hydroxy  and  Ketone  Acids  241 

As  was  stated  above,  sodio-aceto-acetic  ester  may  have 
either  of  two  structures  : 

CH3— C=CH— COOC2H5 


)Na  or   CH3— CO— CHNa— COOC2H5 

Enol  form  Keto  form 

When  an  acid  chloride  reacts  with  sodio-aceto-acetic 
ester,  it  is  possible  to  obtain  at  will  a  compound  in 
which  the  acetyl  group  is  linked  directly  to  carbon  or 
through  oxygen  to  carbon. 

CH3— C=CH— COOC2H5       CH3— CO— CH— COOC2H5 

I  I 

O— COCH3  CO— CH3 

O-derivative  C-derivative 

(Insoluble  in  alkali)  (Soluble  in  alkali) 

When  the  sodio-aceto-acetic  ester  is  treated  directly  with 
acetyl  chloride,  the  C-derivative  only  is  formed.  This 
compound  is  soluble  in  alkali  since  the  hydrogen  in  the 
CH  group  is  linked  to  three  negative  radicals,  two  acetyl 
and  one  carbethoxyl  groups.  (Compare  malonic  ester.) 
When,  however,  the  aceto-acetic  ester  is  mixed  with 
pyridine  and  the  acetyl  chloride  added  to  the  mixture, 
the  O-derivative  only  is  formed. 

As  a  general  rule  the  solubility  in  alkali  of  such  deriva- 
tives as  result  from  the  condensation  of  halogen  com- 
pounds with  metallic  compounds  of  substances  which 
show  tautomerism  is  accepted  as  evidence  of  the  formation 
of  the  C  type  of  derivative,  since  solubility  in  alkali  should 
be  expected  where  there  is  an  active  hydrogen  atom  which 
would  permit  the  formation  in  alkali  of  a  sodium  or 
potassium  derivative. 


242     Organic  Chemistry  for  Students  of  Medicine 


The  study  of  a  large  number  of  such  compounds  has 
revealed  some  in  which  the  change  from  the  keto  into  the 
enol  form  or  vice  versa  takes  place  slowly  even  in  solution, 
and  a  few  where  one  form  is  a  solid  and  is  stable  except 
in  solution.  It  has  been  found  that  the  enol  form  gives 
an  intense  color  reaction  with  ferric  chloride  and  that 
the  keto  form  does  not.  This  serves  as  an  easy  test  for 
identifying  a  tautomer. 

128.   Mesoxalic  acid, 

COOH 

is  formed  when  dibrom  malonic  ester  is  boiled 

CO         with  barium  hydroxide  solution,  the  two  bromine 

atoms  being  replaced  by  hydroxyl  groups : 
COOH 


COOC2H{ 


CBr2 


COOCsH, 


COOC2H. 


Ba(OH)2  =  C< 


COOC2H£ 


COOC2H5 


=      CO  +  H2O 


COOC2H5 


We  have  here  another  instance  of  the  ability  of  one  car- 
bon atom  to  hold  two  hydroxyl  groups  when  it  is  in  close 
proximity  to  strongly  negative  radicals  (compare  glyoxylic 
acid  and  chloral  hydrate).  Mesoxalic  acid  is  consider- 
ably more  unstable  than  malonic  acid,  for  on  boiling  with 
water  it  separates  carbon  dioxide  and  forms  glyoxylic 

acid : 

/OH  ™       CH(OH)2 


H— C^-COOH 
X)H 


-CO, 


COOH 


Hydroxy  and  Ketone  Acids 


243 


Mesoxalic  acid  is  of  biological  interest  owing  to  its 
relation  to  the  formation  of  alloxan  (140). 

129.  Levulinic  Acid,  CH3— CO— CH2— CH2— COOH,  is 
a  7-ketonic  acid  of  interest  because  it  is  formed  by  the 
decomposition  of  sugars  by  means  of  strong  hydrochloric 
acid.  Its  structure  is  revealed  by  its  formation  by  the 
condensation  of  sodio-aceto-acetic  ester  with  chloracetic 
acid  ester,  followed  by  the  ketone  decomposition: 


CH3— CO— CH  Na+Cl  —  CH2— COOC2H5 


COO 

C2H5 
OH 

COOC2H5 

=  CH3— CO— CH— CH2— COOC2H6 


H 


=  CH3— CO— CH2— CH2— COOC2H5 

Levulinic  ethyl  ester 

Levulinic  acid  is  crystalline.  It  melts  at  33.5°  and 
boils  with  some  decomposition  at  250°.  It  behaves  like 
the  typical  ketones  in  yielding  an  oxime,  a  cyanhydrin, 
and  a  hydrazone  (37). 

Levulinic  acid  when  ingested  in  amounts  above  five  to 
six  grams  is  excreted  Unchanged  in  the  urine. 

130.  Oxalacetic  Acid  is  obtained  through  the  Claisen 
synthesis  by  the  condensation  of  ethyl  oxalate  with  ethyl 
acetate  in  the  presence  of  sodium  ethylate  (127). 

.0  /ONa 

C2H5OOC— Cf        +NaOC2H5  =C2H5OOC— C^< 
XOC2H5 

Diethyl  oxalate  Addition  product 


244    Organic  Chemistry  for  Students  of  Medicine 

H 

r\  TT  r\C\C* C*/       C\C*  tl     J_TJ  ^r^ C*C\C\C*  TI 

\^i£\$J\j\j — L>;r —  LJLy2li5-rrl  ~/v^ — l^vAJL,2±l5 


/ONa 
=  C2H5OOC— C< 

I  ^CH— COOC2H5 
IA      B 

C2H5OOC— C04-CH24-COOC2H6 

Like  aceto-acetic  ester  oxalacetic  ester  can  hydrolyze 
in  two  ways  (127)  at  the  points  indicated  by  A  and  B. 
The  first  is  accomplished  by  treatment  with  alkalies  and 
yields  oxalic  and  acetic  acids;  the  second  is  effected  by 
the  action  of  dilute  sulphuric  acid  and  leads  to  the  forma- 
tion of  pyruvic  ester  (67),  carbon  dioxide  and  alcohol. 

131.  Acetone  Dicarboxylic  Acid,  COOH— CH2— CO— 
CH2 — COOH,  results  from  the  nitrile  formed  by  the  action 
of  potassium  cyanide  upon  symmetrical  dichloracetone : 

CH2C1+KCN    CH2— CN  CH2— COOH 

CO  -^CO  +4H2OCO  +2NH3 


CH2C1+KCN    CH2— CN  CH2— COOH 

Dichlor  Acetone  dicyanide  Acetone  dicarboxylic  acid 

acetone 

It  is  also  formed  by  the  action  of  strong  dehydrating 
agents  upon  citric  acid,  a  fact  which  gives  a  clue  to  the 
structure  of  the  latter  acid.  Citric  acid  is  formed  from 
acetone  dicarboxylic  acid  by  the  addition  of  hydrocyanic 
acid  and  subsequent  hydrolysis  of  the  oxynitrile. 


Hydroxy  and  Ketone  Acids  245 

132.  Citric  Acid.  —  As  stated  above,  the  nitrile  of  citric 
acid  is  formed  by  the  cyanhydrin  formation  from  acetone 
dicarboxylic  acid : 

CH2— COOH 
CH2— COOH 

I  /OH 

CO  +HCN  =  C< 

|  XCN 

CH2— COOH 

CH2— COOH 

Cyanhydrin  of  citric  acid 


+2H20      c 


CH2— COOH 
OH 

COOH 

+NH3 
:H2— COOH 


The  reverse  reaction  by  which  citric  acid  is  converted 
into  acetone  dicarboxylic  acid  by  dehydrating  agents  is 
as  follows : 

CH2— COOH     CH2— COOH 

^,    -*  CO       +C0+H20 


CH2— COOH    CH2— COOH 


Citric  acid  occurs  in  the  juice  of  many  plants,  espe- 
cially in  lemon  juice,  from  which  five  per  cent  or  more  may 
be  obtained,  and  in  gooseberries,  which  contain  about  one 
per  cent.  It  is  also  a  normal  constituent  of  the  milk  of 


246     Organic  Chemistry  for  Students  of  Medicine 


animals,  but  it  is  not  certain  whether  it  comes  from  the 
food  or  is  the  product  of  the  milk  glands.  It  has  also 
been  detected  in  certain  grains,  and  is  therefore  one  of  the 
most  widely  distributed  compounds  in  nature.  It  crys- 
tallizes with  one  molecule  of  water  in  large  colorless 
prisms.  When  it  loses  its  water  of  crystallization  through 
heating,  it  forms  a  fine  white  powder. 

It  is  formed  by  the  fermentative  action  of  certain 
bacteria  and  molds,  but  the  nature  of  the  chemical  pro- 
cess by  which  it  is  produced  from  sugars  is  not  clear,  since 
the  sugars  all  contain  the  normal  carbon  chain  whereas 
citric  acid  contains  a  branched  carbon  chain.  It  has 
been  suggested  that  citric  acid  may  result  in  fermentation 
by  the  condensation  with  loss  of  water  from  three  mole- 
cules of  glycolic  acid: 


HO|H2C— COOH 


CH2— COOH 


HO-€-€OOH 
I 


/ 


N 


OH 
COOH 


Three  molecules  of  glycolic  acid 


CH2— COOH 

Citric  acid 


CHAPTER   XII 


UXSATURATED  DIBASIC   ACIDS 
Maleic  and  Fumaric  Acids  and  Their  Is&merism 

133.  There  appears  to  be  good  evidence  that  two  carbon 
atoms  bound  together  by  a  single  bond  are  able  to  rotate 
freely  about  their  common  axis.  Thus  only  one  ethylene 
chloride,  CH2C1 — CH2C1,  is  known.  If  free  rotation  of 
the  carbon  atoms  in  Figure  20  were  not  possible  we  should 
expect  three  modifications  of  this  compound  to  exist : 


If,  however,  free  rotation  of  the  carbon  atoms  about 
their  common  axis  is  assumed,  the  three  arrangements 
of  the  chlorine  atoms  represent  phases  of  intramolecular 
movement  and  not  stable  positions  of  the  tetrahedra. 
It  is  not  necessary  to  assume  a  continuous  movement 

247 


248    Organic  Chemistry  for  Students  of  Medicine 


of  rotation.  In  fact  we  should  expect  that  some  one 
arrangement  of  the  atoms  would  be  more  stable  than  any 
other,  and  that  if  the  atoms  were  arranged  in  any  way 
whatever  they  would  return  to  the  stable  position  and 
any  movement  within  the  molecule  would  constitute  an 
oscillation  about  the  stable  position  (82). 

Such  freedom  of  motion  of  one  carbon  atom  with  re- 
spect to  another  is  in  part  lost  when  the  double  bond  is 


COOH 
HOOC 


Ethylene 


__„ COOH    __ 

Cis  form 

FIG.  21.  —  Maleic  and  Fumaric  Acids. 


COOH 

Trans  form 


established,  as  was  pointed  out  in  discussing  the  isomerism 
of  the  crotonic  acids  (86).  Assuming  that  in  the  case  of 
the  double  bond  the  tetrahedra  which  represent  the 
carbon  atoms  are  in  the  position  which  is  illustrated  by 
their  having  one  edge  in  contact,  ethylene  would  be 
represented  by  Figure  21.  In  such  a  molecule  we  should 
expect  two  modifications  of  ethylene  dicarboxylic  acid : 

CH— COOH  CH— COOH 

II  or  || 

CH— COOH       HOOC— CH 

The  carboxyl  groups  may  be  arranged  on  the  same  or  on 
opposite  sides  of  the  molecule.  Since  in  compounds  of 


Unsaturated  Dibasic  Acids  249 

this  type  there  is  no  asymmetric  carbon  atom,  optical 
activity  is  not  to  be  anticipated.  Theory  agrees  with 
experience,  which  shows  that  fumaric  and  maleic  as  well 
as  the  crotonic  acids  (86)  do  not  rotate  the  plane  of  polar- 
ized light. 

Ethylene  dicarboxylic  acid  results  from  malic  acid 
(122)  by  the  withdrawal  of  a  molecule  of  water.  Its  rela- 
tion to  succinic  and  tartaric  acids  is  shown  by  the  follow- 
ing reactions  : 

COOH  COOH  COOH  COOH 


-HO      ««-   "'  2AgOH  HOH 

CH2      >  CH       *  CHBr  '    ~*  CHOH 

I          I          I  I 

COOH      COOH      COOH       COOH 

Malic  acid  Maleic  and  Dibrom  succinic  Tartaric 

fumaric  acids  acid  acid 

The  decision  as  to  which  of  the  configurations  in  Figure 
21  is  to  be  assigned  to  maleic  and  which  to  fumaric  acid 
is  determined  by  the  following  data  :  Both  are  produced 
from  malic  acid  by  splitting  off  water,  but  the  conditions 
under  which  the  reaction  is  effected  determines  the  nature 
of  the  product.  When  the  temperature  of  malic  acid  is 
raised  to  140-150°  and  maintained  there  during  40  hours, 
fumaric  acid  is  the  principal  product.  When,  however, 
the  malic  acid  is  contained  in  a  distillation  flask  connected 
with  a  condenser  and  the  temperature  is  quickly  raised 
to  200°,  there  distills  over  the  anhydride  of  maleic  acid 
together  with  water. 

Fumaric  acid  does  not  melt  when  heated,  but  sublimes. 


250     Organic  Chemistry  for  Students  of  Medicine 

It  is  but  slightly  soluble  in  water>  1  part  dissolving  in 
148.7  parts  at  16.5°.  It  does  not  form  an  anhydride 
which  on  taking  up  water  regenerates  fumaric  acid,  but 
when  heated  to  the  point  of  decomposition  forms,  along 
with  considerable  charring,  maleic  acid  and  its  anhydride. 

Maleic  acid  is  soluble  in  2  parts  of  water,  at  1.0°.  It 
readily  forms  an  anhydride  which  takes  up  water,  regen- 
erating maleic  acid.  When  maleic  acid  is  heated  in  a 
sealed  tube  in  aqueous  solution  to  210°  it  is  converted 
partially  into  fumaric  acid.  Since  both  acids  contain  the 
same  percentages  of  carbon,  hydrogen,  and  oxygen,  both 
absorb  the  same  amount  of  halogen  (2  atoms)  and  yield 
halogen-substituted  succinic  acids  and  both  result  from 
malic  acid  by  the  loss  of  one  molecule  of  water,  it  is  evi- 
dent that  their  difference  is  a  stereochemical  one. 

The  dibrom  succinic  acids  are  not  identical.  That 
derived  from  fumaric  acid  is  called  dibrom  succinic  acid, 
and  is  but  slightly  soluble  in  water.  That  derived  from 
maleic  is  called  isodibrom  succinic  acid,  and  is  much  more 
soluble  in  water. 

Since  fumaric  acid  does  not  form  an  anhydride,  it  would 
appear  that  of  the  two  possible  positions  which  the  COOH 
groups  may  occupy  in  Figure  21,  the  most  probable  one  is 
that  which  separates  them  most.  This  separation  should 
interfere  with  the  abstraction  of  water  from  the  two 
groups,  and  therefore  to  fumaric  acid  the  trans  structure 
has  been  assigned.  Maleic  is  therefore  the  cis  form. 

HOOC— C— H  H— C— COOH      H— C— CO 

^^O 
H— C— COOH      H-<:-€OOH      H— C— CO 

Fumaric  acid        *  Maleic  acid  Maleic  anhydride 


Unsaturated  Dibasic  Acids 


251 


Another  interesting  observation  which  confirms  the 
belief  in  the  structures  assigned  to  these  acids  is  the  fol- 
lowing :  Both  fumaric  and  maleic  acids  add  two  atoms  of 
-COOH  -  COOH 


Maleic  acid 
FIG.  22. 


COOH 


Isodibrom  succinic  acid 
FIG.  23. 


bromine,  but  as  stated  above  the  dibrom  addition  products 
are  not  identical.     The  mechanism  of  this  addition  in  the 


HOOC 


COOH 


COOH 


Brom  fumaric  acid 
FIG.  25. 


case  of  maleic  acid  is  made  clear  from  an  inspection  of 
Figures  22-25. 

The  addition  of  bromine  may  take  place  at  A  and  A7 
or  at  B  and  B'.     In  either  case  the  same  compound  would 


252     Organic  Chemistry  for  Students  of  Medicine 

result.  If  now  in  Figure  24  hydrobromic  acid  is  sepa- 
rated from  the  isodibrom  succinic  acid,  and  a  double  bond 
again  established,  it  must  involve  the  rotation  of  the 
carbon  atom  represented  by  one  tetrahedron  through  120° 
in  order  to  bring  H  and  Br  together.  This,  together  with 
the  folding  of  the  two  tetrahedra  together,  brings  the  two 
carboxyl  groups  into  the  trans  position,  and  there  results, 
from  maleic  acid,  bromfumaric  acid.  In  a  perfectly 
analogous  manner  there  should  result  from  fumaric  acid, 
by  the  addition  of  two  bromine  atoms,  followed  by  the 
abstraction  of  hydrobromic  acid,  brom  maleic  acid. 
Experiment  has  demonstrated  that  by  this  process  the  cis 
and  trans  forms  are  transformed  into  the  opposite  isomer. 
Fumaric  acid  occurs  in  nature  in  various  plants.  Maleic 
acid  does  not  occur  in  nature.  Fumaric  acid  serves  as  a 
source  of  energy  for  Penicillium  glaucum  and  Asper- 
giilus  niger,  while  maleic  acid  is  not  utilized  by  these 
molds.  Here  we  see  another  example  of  the  fact  which 
has  been  several  times  emphasized,  that  living  organisms, 
being  themselves  constructed  of  complexes  which  exhibit 
the  peculiarities  of  stereochemical  configuration,  show  a 
decided  preference  for  one  isomer  as  contrasted  with 
another  as  a  source  of  nutriment. 


CHAPTER   XIII 
THE  UREIDES 

Ureides  of  the  Monobasic  Acids 

134.  Acetyl  Urea.  —  Urea,  which  was  treated  as  the 
amide  of  carbamic  acid  (57)  (amino  formic  acid)  may 
also  be  regarded  as  a  substituted  ammonia  in  which  a 
hydrogen  atom  of  ammonia  is  replaced  by  NH2 — CO. 
Urea  does  in  fact  form  a  series  of  compounds  in  which  it 
acts  as  does  ammonia;  thus  it  reacts  with  acid  chlorides 
forming  acetyl,  propionyl,  etc.,  ureas : 

CH3— CO— Cl  +  HHN— CO— NH2 

=  CH3— CO— NH— CO— NH2  +  HC1 

Acetyl  urea 

The  same  derivatives  are  formed  by  the  action  of  urea 
on  acid  anhydrides : 

CH3— CO v  I     Hi HN— CO— NH2 

)o  + 

CH3— CO/  JHJHN— CO— NH2 

=  2  CH3— CO— NH— CO— NH2  +H2O 

These  compounds  are  solids.  Acetyl  urea  forms  silky 
needles  melting  at  214°.  It  is  easily  soluble  in  water  and 
alcohol. 

Diacetyl  Urea,  CH3— CO— NH— CO— NH— CO— CH3, 
is  formed  by  the  action  of  carbonyl  chloride  on  acetamide : 

253 


254    Organic  Chemistry  for  Students  of  Medicine 

Cl 
CH3— CO-NHH       | 

+  CO 
CH3— CO— NHH       | 

Cl 
=  CH3— CO— NH— CO— NH— CO— CH3  +2  HC1 

It  is  slightly  soluble  in  cold  water  and  in  alcohol.  M.  P. 
153°.  On  heating  with  acids  it  is  hydrolized  to  acetic 
acid,  carbon  dioxide,  and  ammonia. 

CHa— CO— jNH— ICO— JNHJ  — CO— CH3 

OHIH  nb     JHH!  OH 

=  2  CH3— COOH  +  CO2  +2  NH3 

135.   Glycoluric  Acid  or  hydantoic  acid  is  formed  by  the 
condensation  of  glycolic  acid  with  urea : 

CH2OH   HHN— CO— NH2   CH2— NH— CO— NH2 

|  +  Urea  =| 

COOH  COOH  +H2O 

Glycolic  acid  Glycoluric  acid 

This  compound  can  further  condense  the  NH2  and  COOH 
groups  with  the  separation  of  water  and  the  formation  of 
a  cyclic  ureide,  hydantoin. 

CH2— NH-CO                   CH2-NH— CO 
COOH         NHH  CO NH 

Hydantoin 

Nearly  all  of  the  amino  acids,  when  introduced  into  the 
animal  body,  are  either  eliminated  unchanged,  as  is  the 


The  Ureides 


255 


case  to  a  considerable  extent  with  the  optical  form  not 
found  in  nature,  or  are  completely  burned  to  carbon 
dioxide,  water,  and  ammonia.  In  the  case  of  methyl- 
amino-acetic  acid  (sarcosine)  (63)  a  part  is  combined  with 
urea  with  the  formation  of  methyl  hydantoin,  the  latter 
appearing  in  the  urine.  The  mode  of  formation  is  prob- 
ably as  follows : 

/CH3  CH2— N— CH3 

CH2— N<  | 

XH     .+  HO— CO— NH2  =  CO-f  2  H2O 

COOH  Carbamic  acid  | 

Sarcosine  CO NH 

Methyl  hydantoin 

136.  Hydantoin  is  formed  by  a  method  entirely  anal- 
ogous to  the  formation  of  urea  from  ammonium  cyanate, 
by  intramolecular  rearrangement. ,  Glycocoll  (glycin)  is 
capable  of  forming  salts  with  acids.  The  glycocoll  iso- 
cyanate,  obtained  by-mixing  glycocoll  sulphate  and  potas- 
sium cyanate,  when  heated  rearranges  into  hydantoic 
acid. 

CH2— NH— CO 
HOOC— CH2— NH2— HOCN   >      \  \ 

Glycocoll  cyanate  COOH          HNH 

Hydantoic  acid 

CH2— NH 


CO— NH 

»          Hydantoin 

The  mother  substance  from  which  hydantoin  is  derived 
may  be  regarded  as  glyoxaline : 


256     Organic  Chemistry  for  Students  of  Medicine 
HN— CH 

HC 

II 
N— CH 

This  ring  structure  is  likewise  referred  to  as  imidazole. 
Hydantoin  is  a  white  crystalline  compound  which  melts 
at  216°.  The  formation  of  substituted  hydantoins  re- 
sults from  the  employment  of  amino  acids  other  than  gly- 
cocoll.  These  derivatives  of  the  amino  acids  are  in  some 
cases  compounds  with  much  more  favorable  properties 
than  the  amino  acids  themselves,  and  serve  a  useful  pur- 
pose in  chemical  work  with  these  substances. 

137.  Allantoin  is  a  urea  derivative  of  hydantoin.  It 
results  from  the  condensation  of  two  molecules  of  urea 
with  one  of  glyoxylic  acid.  Glyoxylic  acid  (55),  although 
it  has  the  properties  of  both  an  acid  and  an  aldehyde, 
always  contains  a  molecule  of  water  and  appears  to  act 
as  if  it  contained  two  hydroxyl  groups  linked  to  one  car- 
bon atom.  The  formation  of  allantoin  is  one  of  the 
reactions  in  which  it  displays  this  property. 


NHH     HO 


-CH-JOH     H|  HN      NH  — CH— NH 


CO 

I 
NH2 

Urea 


CO      OH 


H 


co  =  co 


CO 


NH    NH2     CO—  NH 


Allantoin 


Glyoxylic  acid 

Allantoin  is  a  constituent  of  various  tissues  of  animals, 
occurring  in  small  amounts.  It  is  a  constant  constitu- 
ent of  the  urine  of  various  animals,  much  more  in  other 


The  Ureides  257 

animals  than  in  man.  Allantoin  is  a  crystalline  com- 
pound having  neither  taste  nor  odor.  Its  solutions  are 
neutral  to  litmus.  It  dissolves  in  160  parts  of  cold 
water,  but  much  more  reaclily  in  hot  water  or  hot  alcohol. 
It  melts  with  decomposition  at  231°.  It  is  precipitated 
by  silver  in  ammoniacal  solutions,  but  the  precipitate  is 
soluble  in  excess  of  ammonia.  Lead,  copper,  and  mercury 
likewise  form  insoluble  compounds  with  it.  It  reduces 
Fehling's  solution  and  is  a  disturbing  factor  in  the  em- 
ployment of  this  reagent  as  a  test  for  sugars  in  the 
urine. 

On  hydrolysis  with  acids  or  alkalies  allantoin  yields 
ammonia,  carbon  dioxide  (from  the  urea  complexes),  and 
acetic  and  oxalic  acids.  Its  identification  is  effected  by 
its  isolation  as  the  silver  compound,  which  contains 
40.73  %  of  silver  and  by  a  positive  qualitative  test  for 
oxalic  acid  after  hydrolysis  of  a  sample. 

138.  Histidine.  —  The  glyoxaline  or  imidazol  ring 
structure  is  present  in  one  of  the  amino  acids  derived 
from  the  hydrolysis  of  many  proteins,  viz.  histidine: 


CH-NH  CH—  NH  CH—  NHV 

CH 


C-   -N  C  -- 


CH2  CH2                         CH 

I  I                              II 

CHNH2  CH2NH2                   CH 

Histamine  I 

COOH  (S£ftS£)                COOH 

Histidine  Urocanic  acid 

/a-amino-/3-imidazole-\  //3-imidazole-\ 

V       propionic  acid       /  \acrylic  acid/ 


258    Organic  Chemistry  for  Students  of  Medicine 

Histidine  crystallizes  in  platelets  which  melt  at  253° 
with  decomposition.  It  dissolves  readily  in  water,  very 
slightly  in  alcohol,  and  not  at  all  in  ether.  Its  solution 
is  alkaline  to  litmus.  It  forms  salts  with  acids,  the  mono- 
and  dihydrochlorides  being  of  special  importance  in  its  iso- 
lation. It  is  precipitated  from  its  solutions  alkaline  with 
sodium  carbonate  by  mercuric  chloride ;  by  silver  nitrate 
and  ammonia  or  barium  hydroxide ;  by  mercuric  sulphate 
in  sulphuric  acid  solution ;  and  by  phosphotungstic  acid. 

Only  1-histidine  occurs  in  nature.  It  has  a  sweet 
taste.  Putrefactive  bacteria  cause  the  elimination  of 
carbon  dioxide  from  it  with  the  formation  of  histamine, 
or  yS-imidazole-ethylamine.  While  histidine  itself  is 
one  of  the  essential  amino  acids  which  must  be  present 
in  the  food  proteins,  and  can  be  introduced  into  the  body 
without  disturbance,  histamine  is  a  base  which  possesses 
most  marked  physiological  action.  Its  action  is  pri- 
marily a  stimulant  effect  on  plain  muscle.  One  part  in 
25  millions  of  Ringer's  solution  induces  distinct  contrac- 
tions in  a  non-pregnant  uterus.  Larger  doses  induce 
tonic  contraction. 

Histamine  dihydrochloride,  CsHgNs .  2  HC1,  is  read- 
ily soluble  in  water,  but  sparingly  in  ethyl  alcohol.  It 
crystallizes  in  prisms  which  melt  at  140°.  The  base 
forms  a  double  salt  with  hydrochloro  platinic  acid  which 
is  soluble  in  hot  water  but  very  slightly  soluble  in  alcohol. 
On  boiling  with  bromine  water  histamine  gives  a  claret 
color.  It  is  precipitated  by  phosphotungstic  acid,  by 
ammoniacal  silver  solutions,  and  in  alkaline  solutions  by 
mercuric  chloride. 


|| 
CH 


The  Ureides  259 

Urocanic  acid  or  ^-imidazole  acrylic  acid  has  been  found 
in  the  urine  of  dogs,  where  it  probably  has  its  origin  from 
histidine.  It  is  not  a  normal  constituent  of  the  urine 
of  the  dog,  but  probably  represents  an  abnormal  type  of 
metabolism. 
Pyrazole, 

differs  from  imidazole  in  that  the  two 
nitrogen  atoms  in  the  ring  are  in  position 
N  CH  adjacent  to  each  other.  It  is  of  impor- 
tance  in  medicine  because  of  its  derivative, 
phenyl-dimethyl-pyrazolone,  called  antipy- 
rine  and  phenazone.  Methyl-phenyl-pyrazolone  is  formed 
by  the  action  of  phenyl  hydrazine  on  aceto-acetic  ester  : 

CH3—  CO  H2N 

I  +      I 

H2C—  CO—  OC2H6     HN—  C6H6 

CH3—  C=NX 

;N—  C6H6  +  H2O  +  C2H5OH 
H2C—  CO/ 

Antipyrine    is   formed   in   an   analogous   manner    from 
methyl-phenyl-hydrazine. 

Ureides  of  the  Dibasic  Acids 

139.  Oxaluric  Acid  and  Parabanic.  —^  Oxalic  acid  unites 
with  urea  with  the  separation  of  one  molecule  of  water 
according  to  the  following  equation: 


COIOH  +  H|HN-CO-NH2      CO-NH-CO-NH2 
COOH  COOH 


Oxaluric  acid 


260     Organic  Chemistry  for  Students  of  Medicine 

This  type  of  compound  is  known  as  acid  ureide. 

It  is  not  found  practicable  to  stop  the  condensa- 
tion of  oxalic  acid  and  urea  at  this  stage.  Oxaluric 
acid  may  be  prepared  by  the  careful  hydrolysis  of 
parabanic  acid. 

A  second  molecule  of  water  may  be  separated  with  the 
formation  of  a  cyclic  compound : 

CO NH  CO— NH 


CO 


-H20 


CO 


CO|QH    H|NH  CO— NH 

Oxaluric  acid  Parabanic 

(Acid  ureide)  acid 

Parabanic  acid  is  the  simplest  of  the  ureides. 

Oxaluric  acid  occurs  in  the  urine  in  traces.  It  is  a 
white  crystalline  compound  soluble  with  difficulty  in 
water.  On  warming  with  alkalies  it  is  hydrolyzed  to 
oxalic  acid  and  urea. 

Parabanic  acid  is  likewise  crystalline  and  is  much  more 
soluble  than  oxaluric  acid.  Parabanic  acid  is  obtained 
by  the  oxidation  of  uric  acid.  Since  its  structure  was 
understood  from  its  synthesis  from,  and  hydrolysis  to, 
oxalic  acid  and  urea  it  served  to  give  a  clue  to  the  struc- 
ture of  the  more  complex  uric  acid  molecule. 

Ureides  are  also  yielded  by  malonic,  tartronic  and  mesox- 
alic  acids.  They  are  hydrolyzed  to  urea  and  the  acids 
from  which  they  were  derived  on  boiling  with  acids  or 
alkalies,  the  urea  breaking  down  into  ammonia  and  carbon 
dioxide.  Their  structures  are  illustrated  by  the  following 
formulae : 


The  Ureides  261 

CO— NH  CO— NH  CO— NH 

II  II  II 

H2C       CO  HCOHCO  CO    CO 

CO— NH  CO— NH  CO— NH 

Barbituric  acid  Dialuric  acid  Alloxan 

(Malonyl  urea)  (Tartronyl  urea)  (Mesoxalyl  urea) 

Malonyl  urea  is  of  special  interest  because  of  the  nar- 
cotic effect  of  certain  of  its  derivatives.  The  compound 
itself  is  without  noticeable  physiological  action.  Numer- 
ous derivatives  have  been  prepared  by  substituting  one 
or  both  hydrogen  atoms  of  the  malonyl  group  by  alkyl 
and  other  groups.  The  following  selected  list  will  illus- 
trate the  remarkable  influence  which  is  exerted  by  cer- 
tain groups  as  compared  with  others  on  the  pharmaco- 
logical action.  Especially  marked  is  the  effect  of  accu- 
mulating alkyl  groups,  and  the  position  occupied. 

CO— NH  CO— NH  CO— NH 


c 


CHC 


C2H6' 
CO-NH  CO-NH  CO-NH 

Monoethyl  Dimethyl  Diethvl 

malonyl  urea  malonyl  urea  malonyl  Srea 

(1)  (2)  L    e(3)na) 

CO— NH  CO— N— CHa 


C3H7\ 

>C       CO  >C       CO 

C3H/|         |           QH/l  I 

CO— NH  CO-NH 

Dipropyl  Diethyl-N-methyl 

malonyl  urea  malonyl  urea 

(4)  (5) 


262     Organic  Chemistry  for  Students  of  Medicine 

When  the  derivatives  (1)  and  (2)  above  were  given  to  dogs 
weighing  6-8  kilograms,  in  doses  of  3  to  4  grams,  there 
was  no  noticeable  effect.  The  diethyl  derivative  (3)  in 
doses  of  1-15  gm.  induced  deep  sleep  in  about  thirty  min- 
utes, lasting  24  hours.  Of  the  dipropyl  derivative  (4)  a 
1-gram  dose  produced  sleep  after  30  minutes,  lasting  48 
hours,  and  2  grams  induced  sleep  within  15  minutes,  and 
death.  The  toxic  influence  of  introducing  into  diethyl 
barbituric  acid  (3)  a  methyl  group  linked  to  nitrogen  as 
in  (5)  is  very  marked.  A  1-gram  dose  induced  sleep  in 
10  minutes  which  lasted  two  days  and  ended  in  death. 
Veronal  and  a  few  other  similar  compounds  have  found 
use  as  hypnotics. 

140.  Alloxan,  or  mesoxalyl  urea,  is  formed  from  the  oxi- 
dation of  uric  acid.  On  treatment  with  alkali  it  is  hydro- 
lyzed  to  mesoxalic  acid  and  urea. 

CO— NH  COOH      NH2 

II  II 

CO     CO  +  2  H2O  =  CO       +  CO 

II  II 

CO— NH  COOH      NH2 

On  boiling  alloxan  with  dilute  nitric  acid  it  is  oxidized 
to  parabanic  acid  and  carbon  dioxide.  This  is  an  example 
of  the  transformation  of  a  six-membered  ring  to  one  con- 
taining but  five  (113). 

The  formation  of  alloxan  by  the  oxidation  of  uric  acid 
served  as  further  evidence  as  to  the  structure  of  a  part  of 
the  molecule  of  that  substance. 

On  reduction  alloxan  yields  a  derivative,  alloxantine, 
containing  two  alcohol  groups,  which  has  double  the  molec- 


The  Ureides  263 

ular  weight  of  alloxan  itself.     The  structure  assigned  to 
it  is  the  following. 


CO     C  c       CO 

NH—  CO  CO—  NH 

Alloxantine 

When  alloxantine  is  treated  with  ammonia,  it  forms  a 
salt-like  derivative  which  is  a  purple-red  dye  called 
murexide.  Murexide  decomposes  on  hydrolysis  into  uramil 
and  alloxan. 

NH—  CO  CO—  NH      NH-CO  CO—  NH 

I          I/NH\I         III  II 

CO     C^         ^C       CO-*  CO     CHNH2+CO    CO 

NH—  CO  CO—  NH      NH—  CO  CO—  NH 

Murexide  Uramil  Alloian 


CHAPTER   XIV 
THE  PYRIMIDINES,  PYRAZINES  AND  PURINES 

141.  The  Pyrimidines.  In  the  nuclei  of  animal  and 
plant  cells  occur  the  nucleic  acids,  complex  compounds 
which  on  hydrolysis  yield  phosphoric  acid,  purines  (147), 
pyrimidines,  and  a  carbohydrate  group  (163).  There  have 
been  found  in  nucleic  acids  three  representatives  of  the 
pyrimidines : 

1NH— 6CO  N=— C— NH2          NH— CO 

II  II  II 

2CO     5C— CHs          CO     CH  CO     CH 

I          II  I          II  I         II 

3NH— 4CH  NH— CH  NH— CH 

2,  6-diqxy-5-methyl  2-oxy-6-amino  2,  6-dioxy 

pyrimidine  pyrimidine  pyrimidine 

(Thymine)  (Cytosine)  (Uracil) 

In  the  oxy  pyrimidines  there  appears  to  be  in  the  dis- 
solved state  a  dynamic  equilibrium  between  the  mole- 
cules in  which  the  oxygen  is  linked  doubly  to  carbon,  the 
keto  form,  with  the  enol  form  in  which  oxygen  is  singly 
linked  to  carbon  and  is  in  union  with  hydrogen  forming 
a  hydroxyl  group : 

NH— CO  N=C— OH 


264 


The  Pyrimidines,  Pyrazines  and  Purines    265 

When,  e.g.,  uracil  is  acted  upon  by  phosphorus  oxy- 
chloride,  the  oxygen  atoms  are  not  replaced  by  two  chlorine 
atoms,  but  chlorine  replaces  hydroxyl,  and  2,6-dichlor 
pyrimidine  results.  This  can  be  reduced  to  pyrimidine 
itself.  N===C_C1  N=CH 

II  II 

Cl— C     CH     +4H  =  HC     CH 

II      II  II      II 

N— CH  N— CH 

2, 6-dichlor  pyrimidine  Pyrimidine 

Thymine  and  cytosine  are  obtained  from  animal  nu- 
cleic acids,  and  uracil  and  cytosine  from  plant  nucleic 
acids. 

142.  Thymine,  C5H6O2N2,  is  difficultly  soluble  in  cold, 
but  readily  in  hot,  water,  and  slightly  soluble  in  alcohol. 
It  is  precipitated  by  silver  nitrate  in  the  presence  of  a  slight 
excess  of  ammonium  or  barium  hydroxide,  the  precipi- 
tate being  soluble  in  an  excess  of  the  alkalies.     It  is 
likewise  precipitated  by  mercuric  chloride  and  nitrate 
in  the  presence  of  sodium  hydroxide.     Phosphotungstic 
acid  does  not  precipitate  it,  but  it  is  readily  carried  down 
where  other  substances  are  precipitated  by  this  reagent. 
Thymine  sinters  when  heated  quickly,  at  318°,  and  melts 
with  the  evolution  of  gas  at  321°. 

143.  Cytosine,  C^gONsftO,  is  soluble  in  129  parts  of 
water  at  25°.     It  crystallizes  from  hot  water  in  prisms 
which  decompose  with  gas  evolution  at  320°-325°.     The 
salts  formed   with  sulphuric   or  hydrochloric   acids  are 
readily  soluble,  those  with  picric  acid  and  hydrochloro- 
platinic  acid  difficultly  soluble  in  water. 


266     Organic  Chemistry  for  Students  of  Medicine 

Cytosine  is  precipitated  by  phosphotungstic  acid  (147), 
and  by  potassium  bismuth  iodide.  It  gives  the  Weidel 
reaction. 

On  treatment  with  nitrous  acid  it  is  converted  into 
uracil.  The  mechanism  of  this  transformation  is  the 
same  as  in  the  conversion  of  methyl  amine  into  methyl 
alcohol  (46).  Here  however  there  exists  an  equilibrium 
between  the  keto  form  usually  written  for  uracil,  and  a 
small  amount  only  of  the  enol  form.  The  apparent  re- 
placement of  the  amino  group  by  oxygen  instead  of  by 
hydroxyl  as  in  the  primary  amines  is  easily  understood 
in  the  light  of  the  behavior  of  urea  and  thiourea  in  the 
pseudo  or  iso  form  (56,  58)  and  of  aceto  acetic  acid  in 
the  enol  and  keto  forms  (127). 

144.  Uracil,  C4H4O2N2,  is  a  white  crystalline  powder 
easily  soluble  in  hot,  difficultly  soluble  in  cold,  water.  It 
dissolves  readily  in  ammonia  but  scarcely  at  all  in  alcohol 
or  ether.  It  is  precipitated  by  mercuric  nitrate,  but  not  by 
phosphotungstic  acid.  It  is  precipitated  under  the  same 
conditions  as  thymine  by  silver  nitrate  and  ammonium  or 
barium  hydroxide.  Uracil  melts  with  decomposition  at 
335-338°.  It  likewise  gives  the  Weidel  reaction. 

Numerous  experiments  in  feeding  animals  with  rations, 
all  the  constituents  of  which  were  known,  have  demon- 
strated that,  although  the  nuclei  of  all  cells  yield  at  least 
two  of  the  three  pyrimidines  just  described,  the  diet  need 
not  contain  any  of  these  complexes.  They  can  be  syn- 
thesized in  the  animal  body  from  certain  of  the  amino  acids 
yielded  by  the  proteins  of  the  food.  The  mode  of  forma- 
tion of  these  compounds  in  the  body  is  not  understood. 


The  Pyrimidines,  Pyrazines  and  Purines    267 

PYRAZINE  DERIVATIVES 

145.  Pyrazines.  The  paradiazines  are  represented  by 
several  products  of  biological  interest.  Amino  aldehydes, 
on  oxidation,  can  condense  to  form  substituted  pyrazines. 
Thus: 


CH3—  CH  CHO 

I  I 

CHO         CH—  CH3+O 


Alanine  aldehyde  "M" 

/-\ 

CH3—  C     CH 
=  3H20+  |      || 

HC     C—  CH, 


N 

Dimethyl  pyrazine 

Amino  acids  are  not  attacked  by  reducing  agents,  but 
their  esters  can  be  reduced  to  amino  aldehydes  by  means 
of  sodium  amalgam. 

An  instance  of  the  occurrence  of  such  a  condensation 
in  the  animal  body  is  the  elimination  in  the  urine  of  2,  5- 
pyrazine-dicarboxylic  acid  after  injection  of  d-fructose,  a 
ketone  sugar  (156),  and  glycocoll  into  the  veins  of  a  rabbit. 
The  mechanism  of  the  reaction  is  easily  understood. 
Fructose  is  known  to  combine  with  ammonia  to  form  fruc- 
tosamine.  This  compound  is  an  amino  aldehyde  which 
condenses  to  the  pyrazine  ring;  thereafter  the  sugar 
complex  is  oxidized  to  the  last  carbon  atom,  which  is 
converted  into  a  carboxyl  group  : 


268    Organic  Chemistry  for  Students  of  Medicine 


C4H9O4—  CH  CHO 

I  t  +0 

CHO        CH—  C4H9O4 


H2N 

Fructoaamine 


N 

=  C4H9O4—  C      CH 

I        ||  +  3H20 

HC      C—  C4H9O4 

\/ 

N 

Fructosazine 

N 

A 

HOOC  -C     CH 

-  >  ||  +  6C02  +  8H20 

HC     C—  COOH 

\/ 

N 

2,  5-pyrazine  dicarboxylic  acid 

Fructosazine  is  oxidized  outside  the  body  by  hydrogen 
peroxide  with  the  formation  of  the  same  2,  5-pyrazine 
dicarboxylic  acid.  The  latter  compound  gives  in  neutral 
or  faintly  acid  solution  with  ferrous  sulphate  a  fine  vio- 
let color  which  is  easily  seen  in  dilutions  of  1  to  100,000 
parts  of  water.  By  means  of  this  reaction  it  has  been 
shown  that  this  pyrazine  derivative  when  introduced 
into  rabbits,  even  in  small  amounts,  passes  into  the 
urine. 


The  Pyrimidines,  Pyrazines  and  Purines     269 

The  above  condensation  is  of  interest  because  it  points 
to  the  possibility  of  the  reaction  of  carbohydrates  in  the 
body  with  certain  intermediary  decomposition  products 
of  the  amino  acids  with  the  formation  of  heterocyclic 
compounds,  i.e.  cyclic  compounds  containing  more  than 
one  kind  of  element  in  the  ring. 

146.  Piperazine  differs  from  pyrazine  in  that  the  double 
linkages  are  eliminated  by  the  addition  of  hydrogen  or 
substituting  groups,  i.e.  it  is  a  reduced  pyrazine. 

N  NH 

^\  /\ 

HC    CH        H2C       CH2 

I      II  II 

HC    CH        H2C       CH2 

\/         •  v 

N  NH 

Pyrazine  Piperazine 

Piperazine  is  formed  by  heating  the  hydrochloric  acid 
salt  of  ethylene  diamine. 

^NH,  HHN                        /NH\ 

CH2  CH2  H2C            CH2 

I  I                  |               |       +2NH3 

CH2  CH2  H2C            CH2 


HHN 

Ethylene  diamine  Piperazine 

Esters  of  the  amino  acids  change  on  standing,  with  the 
separation  of  alcohol,  into  their  cyclic  anhydrides,  substi- 
tuted ketone  derivatives  of  piperazine.  The  change  is 
accelerated  by  heating. 


270     Organic  Chemistry  for  Students  of  Medicine 


HNH 


CH3— CH 


C2H5O  —CO 

I 
HC— CHa 


CO|OC2H 


H 


NH 


Alanine  ester 


NH 

CO      V 
CO    CH— CHa 


NH 

2, 5-dimethyl-diketo 
piperazine 

These  cyclic  anhydrides  have  in  many  cases  much  more 
favorable  properties  for  manipulation,  as  sparing  solu- 
bility, etc.,  than  have  the  amino  acids  themselves.  On 
heating  with  acids  they  are  hydrolyzed  to  the  free  amino 
acids. 

NH 

/\  COOH     NH2 

CO   CH2  |  | 

|        |      +2H2O=CH2      +  CH2 
CH2  CO  |  | 

V      NH2         COOH 

Glycocoll          Glycocoll 
Diketo  piperazine 


^J.J-2     V. 

NH 


THE  PURINES 

147.  The  researches  of  Emil  Fischer  on  uric  acid  made 
clear  the  constitution  of  the  group  of  compounds  known  as 
the  purines.  The  constitution  of  uric  acid  was  arrived  at 
through  the  observation  that  on  oxidation  it  yields 


The  Pyrimidines,  Pyrazines  and  Purines    271 

allantoin  (137).  It  contains  therefore  two  urea  groups 
in  the  molecule.  The  formation  of  parabanic  acid  and 
alloxan,  whose  structures  are  known  from  their  formation 
from  glyoxylic  acid  and  urea,  and  mesoxalic  acid  and  urea 
respectively,  led  to  the  proposal  of  the  following  structural 
formula:  NH— CO 


O     C—  NH\ 

I      II       /co 

NH—  C—  NHX 

Uric  acid 

The  formation  of  allantoin  from  uric  acid,  which  takes 
place  on  oxidation  with  potassium  permanganate  in  sodium 
hydroxide  solution,  may  be  regarded  as  proceeding  through 
the  following  stages  : 

NH—  CO  NH—  CO 

II  II 

CO     C—  NH\       ->  CO     C(OH)—  HNX 

I         II  /CO         I  )CO 

NH—  C—  NHX  NH—  C(OH)—  HN/ 

NHj[COo|Na 


-^CO    C—  (OS)""!—  NH\ 

I     I  /co 

NH-C  --  i(OH)i—  NH/ 

Uroxanic  acid  (stable  in  alkaline  solution) 

NH2 

on  acidifying 


CQ_ 

;co+co2+H2o 

NH—  CH— 

Allantoin 


272    Organic  Chemistry  for  Students  of  Medicine 

Uric  acid  was  synthesized  in  1895  by  Emil  Fischer  by 
the  following  series  of  reactions : 

NH— CO  NH— CO 

II  II 

CO    CH— NH2+HCNO  ->  CO     CH— NH3CNO 

I         I  I         I 

NH— CO  NH— CO 

Uramll  Cyanic  acid  salt  of  uramil 

Urea          NH— CO 
rearrangement 
*  CO     C— NH— CO— NH2 

I          I 
NH— CO 

Pseudo  uric  acid 

|  -H20 
NH-CO 

I         I 
CO     C— NH\ 

I      II       )co 

NH— C— NW 

Uric  acid 

The  second  product  in  this  series  of  reactions  may  be 
looked  upon  as  a  substituted  ammonium  cyanate.  It 
should  be  expected  therefore  to  rearrange  on  heating,  into 
a  substituted  urea  (urea  in  which  one  hydrogen  atom  is 
replaced  by  barbituric  acid),  and  this  is  what  happens. 
On  heating  this  last  product  with  oxalic  acid  it  loses  a 
molecule  of  water,  passing  into  uric  acid. 

Uric  acid  is  present  in  the  urine  of  all  animals.  Among 
birds  and  reptiles  the  greater  portion  of  the  total  nitrogen 
excreted  is  in  the  form  of  ammonium  urate.  Mammals 
excrete  the  greater  part  of  their  waste  nitrogen  as  urea, 
only  1  per  cent  being  eliminated  as  purines  and  this 


The  Pyrimidines,  Pyrazines  and  Purines    273 

mostly  as  uric  acid  and  allantoin.  Among  mammals 
man  occupies  a  peculiar  position  with  respect  to  the  excre- 
tion of  uric  acid.  Studies  of  a  considerable  number  of 
animals  of  diverse  types  have  shown  that  the  greater  part 
of  the  purine  nitrogen  is  eliminated  in  the  form  of  allan- 
toin. In  man  there  is  but  a  trace  of  allantoin  excreted, 
practically  all  of  the  purine  nitrogen  appearing  in  the 
urine  as  uric  acid.  This  finds  its  explanation  in  the  fact 
that  the  reaction  by  which  uric  acid  is  transformed  into 
allantoin,  oxidation  and  hydrolysis,  is  catalyzed  by  a 
specific  enzyme.  This  enzyme,  which  can  be  recognized 
in  a  tissue  by  its  ability,  under  suitably  regulated  condi- 
tions, to  destroy  uric  acid,  is  present  in  the  tissues  of  all 
animals  except  man.  In  the  absence  of  this  catalytic 
agent  the  conversion  of  uric  acid  to  allantoin  goes  on  with 
extreme  slowness. 

Uric  acid  has  been  synthesized  by  a  considerable  number 
of  methods  starting  from  widely  different  materials.  The 
early  synthesis  (1888)  by  Behrend  and  Roosen,  which  is  par- 
ticularly instructive,  is  illustrated  by  the  following  reactions  : 

NH—  CO  NH—  CO      • 

co   CH 


NH—  C—  CH,  NH—  C—  COOH 

4-methyl  uracil  5-nitro  uracil 

4-carbonic  acid 

Potassium  salt  NH—  CO 
heated  to  130° 
-  >  CO     C— 


NH— CH 

5-nitro  uracil 
T 


274    Organic  Chemistry  for  Students  of  Medicine 

Reduction  with    NH— CO  NH— CO 

Sn+HCl                   I               +N203    I 
>  CO     C— NH2  >  CO     C— OH 

I         II  I         II 

NH— CH  NH— CH 

5-amino  uracil  5-oxy-uracil 

NH— CO  HN— CO 

+  Br    I         I             +AgOH    I          I 
>  CO     C— OH  S_>  co     c— OH 


NH— C— Br  NH— C— OH 

4-bi 

NH— CO 


4-brom-5-oxy  4,  5-dioxy  uracil 

uracil 


NH—  CO 

CO     C-OH     HHN          +H2S04  I         I 

C—  NH 


\ 

ratng   i  11  l^O 

NH-C-OH    HHN  NH-C-NH/ 

Uric  acid 

Uric  acid  is  ordinarily  prepared  from  urine.  It  exists 
in  the  urine  in  the  form  of  the  sodium  and  potassium  salts, 
which  are  fairly  soluble.  One  gram  of  dipotassium 
urate  dissolves  in  44  c.c.  of  water  at  room  temperature, 
and  1  gram  of  disodium  urate  in  77  c.c.  The  free  uric 
acid  is  soluble  in  about  4000  parts  of  water  at  room  tem- 
perature. On  adding  hydrochloric  acid  to  urine,  to  a 
distinctly  acid  reaction,  uric  acid  crystallizes  out  usually 
arranged  in  sheaves,  and  greatly  pigmented.  By  dissolv- 
ing in  strong  sulphuric  acid  (35  %)  and  diluting  with 
water  the  acid  crystallizes  out  and  may  thus  be  purified. 

Uric  acid  acts  like  a  dibasic  acid,  forming  two  series  of 
salts,  acid  and  neutral  urates.  The  ammonium,  calcium, 
and  barium  salts  are  more  difficulty  soluble  than  are  those 


The  Pyrimidines,  Pyrazines  and  Purines     275 

of  the  alkalies.  Phosphotungstic  acid  precipitates  uric 
acid  completely,  as  does  also  silver  nitrate  in  ammoniacal 
solution  in  the  presence  of  magnesium  salts.  Cuprous 
oxide  (copper  sulphate  in  the  presence  of  sodium  acid 
sulphite)  forms  an  extremely  insoluble  compound  with 
uric  acid  and  also  with  purine  bases.  The  acid  char- 
acter of  uric  acid  is  due  to  the  existence  in  solution  of  the 
tautomeric  enol  form  in  dynamic  equilibrium  with  the  keto 
form  which  is  illustrated  by  the  usual  structural  formula. 
That  the  reactive  form  of  uric  acid  is  represented  by  the 
enol  formula  is  shown  by  the  fact  that  when  phosphorus 
oxychloride  acts  on  uric  acid,  OH  is  replaced  by  one  chlo- 
rine, whereas  if  the  reaction  took  place  between  the 
chlorinating  agent  and  oxygen  doubly  linked  to  carbon, 
oxygen  should  be  replaced  by  two  chlorine  atoms  (32). 

The  mother  substance  of  uric  acid  and  of  a  series  of 
biologically  important  purine  bases  is  purine: 

N=CH 

I  I 

HC    C  — NHV 

II  II  iTTPI 

y/^\\. 

N-C W 

Purine 

The  order  of  numbering  the  atoms  in  the  purine  nucleus 
for  indicating  the  position  of  substituted  purines  is  as  fol- 

loWS :     IN C  NH— CO 

I         6|          7  II 

2C       5C— Nv  CO     C— NH\ 

i    4 1    /Cs       i     ii      ; 

3N-  -C— N/  NH— C— NH/ 

2,  6, 8-trioxy  purine  (uric  acid) 


276     Organic  Chemistry  for  Students  of  Medicine 

Purine  is  formed  from  trichlor  purine,  which  results 
directly  '  from  the  action  of  phosphorus  oxychloride  on 
uric  acid. 

N  =  C—  OH 

I  I 
HO—  C    C—  NHX 

II  II          >-OH 

N—  C  -  N^ 

Uric  acid  (tautomeric  form) 

N  =  C—  Cl 
C1C     C—  NHX  +H3PO4 

||     ||         ; 

N—  C—  NH/ 


N  =  CH  N  =  CI 

HC    C—  NH  +4H   1C     C—  NH 


N—  C  --  N  N—  C 


Purine  2,  6-diiodo  purine 

The  urea  complexes  behave  in  these  reactions  as  if  they 
had  .the  iso  structure  (57,  58). 

Purine  is  a  crystalline  substance  which  melts  at  211- 
212°.  It  is  a  basic  compound  and  forms  salts  with  various 
acids. 

Hypoxanthine,  C5H4N4O.  —  There  are  besides  uric  acid 
two  other  oxypurines  which  are  of  great  biological  interest, 
viz.  xanthine  and  hypoxanthine.  Their  relation  to  uric 
acid  is  shown  by  their  formulae: 


The  Pyrimidines,  Pyrazines  and  Purines    277 

NH— CO  NH— CO 

II  II 

HC       C— NH\  OC       C— NHk 

II        II           >H                          |         ||  )CH 

N C N^  NH— C N^ 

6-oxy  purine  (Hypoxanthine)  2,  6-dioxy  purine  (Xanthine) 

NH— CO 

I          I 
OC        C— NHV 

I      II        )co 

NH— C— NH/ 

2, 6,  8-trioxy  purine  (Uric  acid) 

Hypoxanthine  is  a  crystalline  compound  soluble  in  69.5 
parts  of  boiling  water  and  in  1400  parts  at  19°.  It  dis- 
solves readily  in  mineral  acids  and  alkalies.  It  is  insoluble 
in  alcohol.  The  hydrochloride,  C5H4N4O .  HC1  +  H2O, 
is  decomposed  on  crystallization  from  water,  but  can 
be  crystallized  from  concentrated  hydrochloric  acid. 
The  sulphate  and  nitrate  are  likewise  decomposed  by 
water.  Hypoxanthine  picrate  is  a  characteristic  salt. 
Hypoxanthine  is  precipitated  from  its  solutions  by 
ammoniacal  silver  nitrate. 

Hypoxanthine  is  found  in  the  muscles  and  organs  of 
the  animal  body  and  is  accumulated  in  beef  extract. 
It  is  likewise  widely  distributed  in  plants. 

Xanthine,  C5H4N4O2,  is  likewise  found  in  animal  tissues 
and  widely  distributed  in  plants.  It  is  very  slightly  sol- 
uble in  water,  about  1  to  14,000  parts  at  16°,  and  in  1400 
parts  of  boiling  water.  It  dissolves  more  readily  in 
alkalies.  Xanthine,  like  hypoxanthine,  forms  salts  with 
acids.  However,  it  also  forms  crystalline  compounds 
with  alkalies. 


278     Organic  Chemistry  for  Students  of  Medicine 

On  evaporation  with  concentrated  nitric  acid,  there 
remains  a  yellow  residue,  which  on  treatment  with  sodium 
hydroxide  becomes  reddish  yellow  and  on  heating  purple- 
red.  This  is  a  modification  of  Weidel's  reaction. 

/ 

AMINO  PURINES 

148.  Adenine,  CsHsNs. — There  is  but  one  amino 
purine  found  in  nature,  viz.  6-amino  purine  or  adenine. 
It  is  a  product  of  the  hydrolysis  of  nucleic  acids  of  both 
plant  and  animal  origin.  It  is  crystalline  and  decomposes 
at  360-365°.  It  is  soluble  in  155  parts  of  water  at  18°. 
It  forms  salts  with  mineral  acids  which  in  contrast  to  those 
of  hypoxanthine  and  xanthine  can  be  crystallized  from 
water.  Its  oxalate  and  picrate  are  characteristic  salts. 
The  latter  serves  to  separate  adenine  from  hypoxanthine. 

Adenine  does  not  give  the  xanthine  or  murexide  tests. 
It  is  best  prepared  from  extracts  of  tea  leaves. 

Adenine  is  usually  associated  with  the  closely  related 
purine  base  guanine,  or  2-amino-6-oxy  purine. 

N  =  C— NH2  NH— CO 

II  II 

HC     C— NHV  H2N— C     C— NH 

>CH  II     II 


N— C— N^  N— C— N^ 

6-amino  purine  2-amino-6-oxy  purine 

(Adenine)  (Guanine) 

Guanine  is  found  widely  distributed  in  both  animal  and 
plant  tissues,  and  is  present  in  nucleic  acids.  It  is  the 
principal  constituent  of  the  excrement  of  spiders,  and  is 
occasionally  found  deposited  as  crystals  in  the  joints  of 
swine  in  the  so-called  "  guanine  gout."  Guanine  is 


The  Pyrimidines,  Pyrazines  and  Purines    279 

insoluble  in  water,  alcohol,  and  ether,  very  slightly  soluble 
in  ammonia,  but  readily  soluble  in  sodium  hydroxide. 
On  the  addition  of  copper  sulphate  and  sodium  bisulphite 
to  its  solutions  the  cuprous  oxide  compound  of  guanine 
is  precipitated  quantitatively.  With  acids  it  forms  salts 
which  crystallize,  but  these  are  stable  only  in  the  presence 
of  an  excess  of  the  acid.  In  water  they  are  decomposed. 
The  metaphosphate,  picrate,  and  silver  nitrate  compounds 
are  useful  in  its  isolation  and  purification.  Adenine  and 
guanine  are  the  only  purines  which  are  present  in  the 
nucleic  acid  molecule.  In  the  body  they  react  with  water 
through  the  catalytic  agency  of  enzymes,  which  accelerate 
the  change,  forming  oxypurines,  from  adenine,  hypoxan- 
thine,  and  from  guanine,  xanthine  : 


C—  NH  +NH3 


N—  C— 

Adenine  Hypoxanthine 

This  transformation  also  occurs  through  the  action  of 
nitrous  acid  on  adenine,  the  amino  group  being  replaced 
by  hydroxyl,  which  passes  in  part  into  the  keto  form. 
Hypoxanthine  can  take  up  an  atom  of  oxygen,  being  con- 
verted into  xanthine  ;  and  xanthine  can  in  like  manner  be 
oxidized  to  uric  acid.  These  deaminations  and  oxidations 
represent  the  course  of  purine  metabolism  in  the  body. 
Guanine  is  hydrolyzed  to  guanidine,  etc.  The  enzymes 
which  effect  these  changes  in  measurable  time  are  specific 
in  character.  Thus  there  is  an  adenase  which  can  deam- 


280     Organic  Chemistry  for  Students  of  Medicine 

inize  adenine  to  hypoxanthine,  and  a  guanase  which  cata- 
lyzes the  transformation  of  guanine  into  xanthine  as  de- 
scribed above.  Not  all  tissues  contain  all  the  enzymes 
necessary  to  the  transformation  of  the  amino  purines 
into  oxy purines.  Thus  adenase  is  not  found  in  the  tissues 
of  the  rat.  Guanase  is  absent  from  the  spleen  and  liver 
of  the  pig  and  from  the  human  spleen,  but  is  present  in 
most  other  tissues.  The  enzyme  which  accelerates  the 
oxidation  of  hypoxanthine  into  xanthine  is  called  hypo- 
xanthine-oxidase ;  that  which  oxidizes  xanthine  to  uric 
acid  is  called  xanthine-oxidase.  The  enzyme  which 
accelerates  the  oxidation  of  uric  acid  to  allantoin  is 
called  uricase.  The  ending  ase  is  employed  to  designate 
enzymes  or  organic  catalysers. 

The  nucleic  acids  of  both  animal  and  plant  origin  con- 
tain but  two  purines,  adenine  and  guanine.  The  hypo- 
xanthine, xanthine,  and  uric  acid  found  in  the  tissues  are 
formed  by  the  deamination  and  oxidation  of  these. 

Within  recent  years  feeding  experiments  with  young 
animals  have  shown  that  with  diets  entirely  free  from 
any  of  the  purines,  growth  and  hence  the  synthesis  of 
nucleic  acids  can  take  place  at  the  normal  rate.  Such 
animals  regularly  excrete  uric  acid.  There  is  no  doubt 
that  in  such  experimental  animals  adenine  and  guanine 
are  produced  synthetically.  The  substances  from  which 
purines  are  formed  in  mammals  are  not  known  with  cer- 
tainty, but  experiments  with  birds  make  it  highly  prob- 
able that  they  are  urea,  ammonia,  and  lactic  acid.  In 
birds  the  seat  of  synthesis  of  uric  acid  is  the  liver.  When 
the  liver  of  a  bird  is  excised  the  bird  has  been  found  to 


The  Pyrimidines,  Pyrazines  and  Purines    281 

excrete,  during  the  few  hours  it  can  live,  ammonia  and 
lactic  acid  instead  of  uric  acid. 

THE  METHYL   PURINES 

149.  Aside  from  the  purines  ingested  as  adenine  and 
guanine  or  their  degradation  products  there  occur  in 
plant  foods  two  important  methylated  purines,  theo- 
bromine  and  caffeine. 

Theobromine  is  2, 6-dioxy-3, 7 '-dimethyl  purine: 

NH— CO 

I          I          /CH3 

CO     C— N<^ 

CH3— N C— N^ 

Occurs  in  the  cocoa  bean,  and  is  found  in  chocolate  to 
the  extent  of  1  to  2  per  cent.  It  is  a  dimethyl  xanthine. 
It  is  a  white  crystalline  powder,  soluble  in  ether,  in- 
soluble in  alcohol  and  water,  but  somewhat  soluble 
in  hot  chloroform.  It  forms  crystalline  salts  with 
strong  acids,  but  these  are  decomposed  into  the  base 
and  acid  by  water.  It  sublimes  unchanged  at  290°. 
It  is  a  powerful  diuretic  and  nerve  stimulant.  It  has  a 
bitter  taste.  The  hydrochloride  and  salicylate  are  also 
much  employed. 

Caffeine  is  2,Q-dioxy-l,3,7-trimethyl  purine: 

CH3— N CO 

I  I 

CO     C— N 

I          II 
CH3— N C— N 


282     Organic  Chemistry  for  Students  of  Medicine 

It  occurs  in  tea  and  coffee,  guarana,  and  in  kola  nuts. 
Coffee  contains  about  one  per  cent.  It  is  soluble  in  80 
parts  of  water ;  55  parts  of  alcohol,  7  parts  of  chloroform, 
and  555  parts  of  ether  at  15°.  Caffeine  crystallizes  from 
water  in  white  fleecy  masses  of  silky  needles,  having  a 
bitter  taste.  It  sublimes  at  178°. 

Caffeine  is  a  diuretic  and  cerebral  stimulant  and  has  a 
pronounced  stimulating  action  on  the  heart. 

In  passing  through  the  body  caffeine  and  theobromine 
are  partially  demethylated,  and  they  appear  in  the  urine 
to  some  extent  as  monomethyl  and  dimethyl  purines. 
In  part  the  methyl  groups  are  completely  removed,  the 
nucleus  being  excreted  as  uric  acid. 


CHAPTER  XV 
THE   CARBOHYDRATES 

150.  There  is  found  in  nature  a  large  group  of  compounds 
to  which  the  general  name  carbohydrates  is  applied.  These 
are  either  aldehyde  alcohols  or  ketone  alcohols,  or  are 
converted  into  aldehyde  alcohols  or  ketone  alcohols  on 
hydrolysis.  The  carbohydrates  include  the  sugars, 
starches,  celluloses,  gums,  pectins,  etc.  In  many  of  them 
the  composition  corresponds  closely  to  the  general  formula 
Cn(H2O)n,  or  one  molecule  of  water  to  each  carbon  atom. 
Thus,  cane  and  beet  sugar  have  the  formula  Ci2H22On 
which  corresponds  to  €12 1 1  (H2O) ;  glucose  and  fructose, 
CeHtfOe  =  C66(H2O);  starch,  the  molecule  of  which  is 
very  large,  corresponds  to  the  formula  CG  5(H2O).  It  was 
from  this  relationship  that  they  received  the  name  carbo- 
hydrate. There  are  several  representatives  of  the  carbo- 
hydrates which  do  not  conform  to  this  formula ;  and  there 
are  on  the  other  hand  a  number  of  compounds  totally 
unrelated  chemically  to  the  carbohydrates  which  contain 
carbon,  hydrogen,  and  oxygen,  the  two  latter  elements  in 
the  proportion  to  form  water.  As  examples  may  be  cited 
formaldehyde,  CH2O,  acetic  acid,  C2H4O2,  and  lactic  acid, 
CaHeOs.  The  carbohydrates  are  of  the  greatest  impor- 
tance as  a  source  of  energy  to  the  animal  body,  and  as  a 
rule  among  the  herbivora  and  omnivora  they  constitute 

283 


284     Organic  Chemistry  for  Students  of  Medicine 

the  greater  part  of  the  diet.  In  man  there  frequently 
occurs  a  pathological  state  (diabetes)  in  which  the  body 
is  incapable  of  oxidizing  carbohydrates,  the  absorbed 
sugars,  wholly  or  in  part,  being  eliminated  unchanged  in 
the  urine.  The  exact  nature  of  this  disorder  is  not  under- 
stood, and  it  is  therefore  of  the  first  importance  that  we 
should  have  a  full  understanding  of  the  chemical  nature 
of  the  carbohydrates  and  of  the  changes  which  they  under- 
go in  the  course  of  normal  metabolism. 

The  classification  of  the  carbohydrates  is  based  upon  the 
fact  that  there  are  found  widely  disseminated  in  nature 
certain  aldoses  and  ketoses  which  contain  six  carbon  atoms, 
called  hexoses  (glucose,  fructose,  etc.)  and  others  called 
polysaccharides  (starches,  dextrine,  cellulose,  etc.)  which 
are  polymers  of  the  hexoses  and  yield  the  latter  on  hydroly- 
sis. Widely  prevalent  also  are  the  pentosans,  polysac- 
charides which  on  hydrolysis  yield  aldopentoses,  or  sugars 
containing  five  carbon  atoms.  The  four  aldohexoses  and 
five  aldopentoses  are  all  aldehydes  and  in  addition  contain 
alcohol  groups  Between  these  pentoses  and  hexoses, 
which  are  termed  monoses,  and  their  complex  polymers, 
are  the  disaccharides,  trisaccharides,  etc.,  yielding  on 
hydrolysis  two,  three,  etc.,  molecules  of  monoses.  The 
term  sugar  is  usually  applied  only  to  mono-,  di-,  and 
trisaccharides. 

Before  discussing  the  chemistry  of  the  carbohydrates  it 
is  necessary  to  describe  in  further  detail  the  behavior  of 
phenylhydrazine  with  several  types  of  compounds.  The 
reaction  of  hydrazine,  NH2 — NH2,  and  its  derivatives  with 
aldehydes  and  ketones  has  already  been  pointed  out 


The  Carbohydrates  285 

(32,  37).  With  compounds  of  the  type  of  acetaldehyde  or 
acetone,  mono  derivatives,  hydrazones,  are  formed.  With 
glyoxal,  phenylhydrazine  reacts  to  form  a  dihydrazone, 
or  osazone. 

CHO   H2N— NH— C6H5   CH=N— NH— C6H5 

+ 
CHO   H2N— NH— C6H5   CH=N— NH— C6H5 

Glyoxal  Phenylhydrazine  Glyoxal  osazone 

The  same  osazone  is  obtained  by  the  action  of  phenyl- 
hydrazine upon  glycolaldehyde,  the  simplest  of  the 
carbohydrates. 

The  reaction  with  glycolaldehyde  takes  place  in  three 
stages,  in  one  of  which  a  hydrazone  is  formed,  in  the  second 
the  adjacent  carbinol  group  is  converted  by  the  with- 
drawal of  two  hydrogen  atoms  into  carbonyl,  with  the 
destruction  of  a  molecule  of  phenylhydrazine.  In  the 
third  step  another  molecule  of  phenylhydrazine  is  con- 
densed with  the  newly  formed  carbonyl  group  producing 
the  osazone. 

CH2OH 

I 
CHO  +  2  H2N— NH— C6H6 


CHO 


Tl 


|H  +H2N|— INK— c6H5 


NH3 


CH  =  N— NH— C6H5  C6H5NH2 

Aniline 

CH  =  N— NH— C6H5 
+H2N— NH— C6H5=| 
CH  =N— NH— C6H5  CH  =  N-NH— C6H5 

Glyoxal  hydrazone 


286    Organic  Chemistry  for  Students  of  Medicine 

This  conversion  of  the  group 

I  I 

CHOH  C=N-NH-C6H5 

into      | 
CO  C=N— NH— C6H5 

I  I 

is  characteristic  of  the  action  of  phenylhydrazine  on  the 
simple  carbohydrates,  and  indicates  that  a  secondary 
alcohol  group  is  attached  to  the  carbon  atom  adjacent  to 
the  aldehyde  group. 

The  observation  of  the  formation  of  osazones  by  the 
sugars  made  possible  the  ready  separation  and  purification 
of  sugars.  The  difficulties  attending  the  crystallization  of 
sugars  from  their  solutions,  owing  to  their  great  solubility 
and  tendency  to  form  sirups,  had  previously  prevented 
rapid  advance  in  the  study  of  the  chemistry  of  the  carbo- 
hydrates. The  osazones  are  difficultly  soluble  in  water, 
crystallize  well,  and  have  definite  melting  points.  The 
latter  property  makes  it  easy  to  identify  the  individual 
sugars. 

The  aldohexoses  all  have  the  formula  CeH^Oe.  They 
all  react  with  phenylhydrazine  in  the  manner  described 
above,  showing  that  they  contain  the  aldehyde  group  and 
a  hydroxyl  in  the  alpha  position  to  it.  Their  aldehyde 
property  is  further  shown  by  the  fact  that  they  exert  a 
reducing  action  on  certain  salts  of  the  heavy  metals,  as 
alkaline  copper  and  bismuth  solutions  and  ammoniacal 
silver  solutions.  They  are  reduced  by  nascent  hydro- 
gen to  hexahydric  alcohols,  and  are  oxidized  to  penta- 
hydroxy  acids  containing  six  carbon  atoms. 


The  Carbohydrates  287 

All  the  aldohexoses  contain  a  normal  carbon  chain. 
This  is  shown  by  the  fact  that  on  reduction  with  hydriodic 
acid  they  yield  a  n-secondary  hexyl  iodide. 

CH2OH 

I 
(CHOH)4+6HI 

CHO 

=  CH3— CH2— CHI— CH2— CH2-CH3+6H20+5I 

This  iodide  can  be  converted  into  a  secondary  alcohol  by 
ordinary  methods  (13,  22)  and  has  been  shown  to  yield  on 
oxidation  ethyl,  propyl  ketone  : 

CH3— CH2— CO— CH2— CH2— CH3 

which  is  oxidizable  to  acetic,  propionic  and  butyric  acids 
(38). 

The  presence  of  five  hydroxyl  groups  is  further  estab- 
lished by  the  fact  that  the  aldohexoses  react  with  acetic 
anhydride  to  form  penta  acetyl  derivatives  (52).  When 
the  latter  are  purified  and  a  weighed  sample  saponified 
with  standard  alkali,  it  is  found  that  the  acetic  acid  formed 
corresponds  with  the  theoretical  amount  for  such  com- 
pounds. 

Since  two  hydroxyl  groups  can  remain  linked  to  a  single 
carbon  atom  only  in  special  cases  when  the  latter  is  in  close 
proximity  to  one  or  more  strongly  negative  radicals  (32, 
55),  none  of  which  exist  in  the  sugar  molecule,  it  is  assumed 
that  the  carbon  atoms  other  than  that  contained  in  the 
aldehyde  group  each  hold  a  single  hydroxyl,  since  the 
hypothesis  that  certain  carbon  atoms  have  linked  to  them 


288     Organic  Chemistry  for  Students  of  Medicine 

more  than  one  hydroxyl  is  untenable.  Each  one  except 
the  end  ones  must  be  linked  on  two  sides  to  carbon  and 
on  one  to  hydroxyl.  The  remaining  bond  must  be  occu- 
pied by  hydrogen.  By  such  reasoning  we  arrive  at  the 
conclusion  that  the  structure  of  the  aldohexoses  is  the 
following : 

CH2OH— CHOH— CHOH— CHOH— CHOH— CHO 

151.    Methods  of  Synthesis  of  the  Monoses.  —  1.  By 

the  carefully  regulated  oxidation  of  the  polyatomic  alco- 
hols. As  an  example  may  serve  the  oxidation  of  glycerol. 
It  has  previously  been  described  (36)  how  by  cautious 
oxidation  of  this  triatomic  alcohol  there  results  glyceralde- 
hyde,  which  in  the  terminology  of  the  carbohydrates  is 
glycerose.  The  chief  product  of  this  reaction  is  always 
the  isomer  dihydroxy  acetone : 

CH2OH  CH2OH  CH2OH 

2  CHOH      +  2<?     CO  +     CHOH  +  2H20 

I  I  I 

CH2OH  CH2OH  CHO 

Glycerol  Dihydroxy  acetone       Glyceraldehyde 

Glyceraldehyde  can  be  prepared  free  from  dihydroxy 
acetone  by  the  oxidation  of  acrolein  (86),  the  aldehyde 
group  of  the  latter  being  protected  during  the  process  by 
first  converting  it  into  the  acetal  (32).  As  in  the  case  of 
the  fatty  acids,  oxidation  of  compounds  containing  doubly 
linked  carbon  leads  first  to  the  formation  of  hydroxy 
groups  at  this  point. 


The  Carbohydrates 


289 


CH2 

II 

CH  + 

/OC2H5        HOH 
CH< 

XOC2H5 

Acrylic  aldehyde  acetal 

CH2OH 

=  CHOH        JL 

I 
CH(OC2H5)2 

Glyceraldehyde  acetal 


CH2OH 

CHOH    +    2  C2H5OH 


CHO 

Glyceraldehyde 


Alcohol 


2.  By  hydrolysis  of  brom  aldehydes  with  barium 
hydroxide.  Mention  has  aleady  been  made  of  the  forma- 
tion of  glycol  aldehyde  from  brom  acetaldehyde  by  this 
method  (35).  By  this  method  glyceraldehyde  may  also 
be  prepared.  Starting  with  acrylic  aldehyde,  two  bromine 
atoms  are  added.  The  dibrom  propyl  aldehyde  reacts 
with  water  when  heated  with  barium  hydroxide,  the 
bromine  atoms  being  replaced  by  hydroxyl. 


CH2 

II 
CH 


,2Rr 
+2ir 


CH2OH 


OH      CHOH 


CHO  CHO  CHO 

3.  When  formaldehyde  is  treated  with  weak  alkali 
(limewater)  it  condenses  to  a  mixture  of  compounds  of 
the  formula  CeHi2O6.  The  mixture  is  sirup-like  and  sweet. 
It  has  received  the  name  formose.  In  its  formation  six 
molecules  of  formaldehyde  condense  to  form  a  mixture  of 
aldohexoses : 


290     Organic  Chemistry  for  Students  of  Medicine 
CH2O  +  HHCO  +  HHCO  +  HHCO  +  HHCO  +  HHCO 

Six  molecules  of  formaldehyde 

=  CH2OH— CHOH— CHOH— CHOH— CHOH— CHO 

Aldohexose 

4.  Dilute  alkalies  cause  two  molecules  of  glyceraldehyde 
to  condense,  forming  an  aldohexose.     It  is  called  acrose. 
Like  synthetic  compounds  in  general  the  hexoses  formed 
by  the  methods   just   described   are   optically  inactive, 
whereas  all  the  sugars  found  in  nature  exhibit  optical 
activity. 

5.  A  most  important  method  discovered  by  Kiliani 
makes  possible  the  building  up  of  tetroses  from  trioses, 
hexoses  from  pentoses,  etc.     It  consists  in  the  addition  of 
hydrocyanic  acid  to  the  aldehyde  group  of  the  pentose, 
forming  an  oxynitrile,  in  a  manner  analogous  to  the  for- 
mation of  lactic  acid  from  acet aldehyde  (66).     The  nitrile 
radical  is  hydrolyzed  to  a  carboxyl  group.     This  in  solution 
forms  a  lactone  with  the  hydroxyl  in  the  7-position  (125), 
and  the  lactone  can  be  reduced   by  means  of  nascent 
hydrogen  (sodium  amalgam)  to  an  aldehyde. 

I  I  I  I 

CHOH       CHOH       CHOH     CHOH 
CHO  +HCI?  CH   +2H*9  CHOH  +2"  CHOH 


N 


'H  COOH  CHO 

CN 

Kiliani's  reaction 

6.  Wohl  discovered  a  method  which  makes  possible  the 
reversal  of  the  preceding  operation  (Kiliani's  reaction) 
and  the  formation,  of  a  sugar  molecule  having  one  less 


The  Carbohydrates  291 

carbon  atom  in  the  molecule  than  is  contained  in  the  sugar 
employed  to  begin  with.  It  involves  (1)  the  formation 
of  an  aldoxime  by  the  condensation  of  hydroxylamine 
with  the  aldehyde  group  (32).  (2)  The  oxime  is  treated 
with  acetic  anhydride  and  sodium  acetate  which  abstracts 
the  elements  of  a  molecule  of  water  from  the  oxime,  form- 
ing a  nitrile  (40).  Incidentally  the  acetyl  derivatives 
of  the  hydroxyl  groups  are  produced.  (3)  Potassium 
hydroxide  removes  the  acetyl  radicals  by  hydrolysis,  and 
on  subsequent  treatment  with  hydrochloric  acid  hydro- 
cyanic acid  is  split  off  with  the  formation  of  an  aldehyde 
group.  The  reactions  will  be  made  clear  by  the  following 
scheme : 

CH2OH  CH2OH 

I              NH2OH 
(CHOH)n >  (CHOH)n 

I  I 

CHOH  CHOH 

I  I 

CHO  CH=N— OH 

CH2OCOGH3 

(CH3CO)2O     I 

— — ->  (CHOCOCH3)n 
—  H2O          | 

CHOCOCHs 

CH2OH 
Hydrolysis  with  HC1 


-HCN;   -CH3— COOH 

CHO 


Wohl's  reaction 


292     Organic  Chemistry  for  Students  of  Medicine 

7.  It  has  also  been  found  that  when  a  simple  sugar,  as  an 
aldohexose,  is  oxidized  carefully,  the  first  product  of  the 
reaction  is  an  acid  having  the  same  number  of  carbon 
atoms.  On  further  oxidation  of  the  calcium  salt  of  this 
with  hydrogen  peroxide  in  the  presence  of  a  little  ferric 
acetate  which  acts  as  a  catalytic  agent,  carbon  dioxide  is 
separated  and  the  alcohol  group  which  in  the  sugar  occu- 
pied the  a-position  to  the  aldehyde  group  is  oxidized  to 
aldehyde.  There  results  the  aldo  sugar  having  one  less 
carbon  atom  than  that  employed  in  the  oxidation. 

CH2OH  CH2OH        CH2OH 

(CHOH)3         (CHOH)3     (CHOH) 


CHOH  CHOI  I         CHO 

Aldopentose 

CHO 

Aldohexose  Hexonic  acid 

The  pentoses  are  readily  distinguishable  from  the 
hexoses  by  their  tendency  to  lose  three  molecules  of  water 
and  pass  into  furfural,  a  cyclic  aldehyde  containing  four 
carbon  atoms  and  one  oxygen  atom  in  its  ring. 

CH2OH 
CHOH 


Furfural  Pyromucic  acid 


CHO 

Pentoae 


The  Carbohydrates  293 

The  structure  of  furfural  is  evident  from  (1)  its  mode  of 
formation,  (2)  its  conversion  into  an  acid,  pyromucic  acid, 
C^OCOOH,  on  oxidation,  (3)  the  formation  of  furfurane 
by  the  loss  of  carbon  dioxide 

CH=CH\  _C02  CH=CH\ 

I  >  -^    | 

CH  =  C(  CH=CH 

\lCOO|H  Furfurane 

on  heating  in  a  sealed  tube  to  275°.  That  furfurane  has  its 
oxygen  in  the  ring  and  not  in  the  form  of  a  carbinol  or 
carbonyl  group  is  shown  by  the  fact  that  with  metallic 
sodium  no  hydrogen  is  evolved,  as  is  the  case  with  the  alco- 
hols (15),  and  it  does  not  react  with  hydroxylamine  or  other 
reagents  with  which  aldehydes  or  ketones  condense.  Fur- 
fural is  an  oily  liquid  with  an  agreeable  odor  which  boils 
at  162°.  With  paper  moistened  with  aniline  acetate  it 
gives  an  intense  red  color. 

Those  carbohydrates  which  contain  an  aldehyde  group 
are  called  aldoses,  and  those  which  contain  a  ketone  group 
ketoses.  The  names  of  the  sugars  end  in  ose  and  those  of 
the  alcohols  which  result  from  the  reduction  of  the  car- 
bonyl group  end  in  He.  Glycol  aldehyde  and  glycerose, 
while  chemically  sugars,  do  not  occur  in  nature  except 
possibly  as  unstable,  transitory,  intermediary  products  of 
the  oxidation  of  the  carbohydrates.  They  are  not  named 
in  accordance  with  the  systematic  nomenclature  of  the 
sugars.  Since  every  representative  of  this  group  of  sub- 
stances contains  in  addition  to  the  carbonyl  group  C=O 


294     Organic  Chemistry  for  Students  of  Medicine 

(aldehyde  or  ketone  group)  at  least  one  carbinol  group 
HCOH,  it  must  follow  that  for  each  of  the  aldoses,  there 

are  two  acids  which  can  be  derived  by  oxidation  and  an 
alcohol  which  can  be  obtained  by  reduction.  The  follow- 
ing resume  of  the  simple  aldoses,  together  with  the  cor- 
responding alcohols  and  acids,  will  serve  to  illustrate  their 
relationships : 

Diose,  C2H4O2 

CH2OH  CH2OH 


CH2OH 
CH2OH 

Glycol 


CHO 

Glycol  aldehyde 


COOH 

Glycolic  acid 


COOH 
COOH 

Oxalic  acid 


Triose  (glycerose),  C3H603 


CH2OH 

1 

CH2OH 

1 

CH2OH 

1 

COOH 

| 

CHOH 

1 

CHOH 

1 

CHOH 

1 

CHOH 

1 

CH2OH 

Glycerol 

CHO 

Glycerose 

COOH 

Gly  eerie  acid 

COOH 

Tartronic  acid 

Tetrose  (erythrose),  C4H804 


:H2OH 

CH2OH 

CH2OH 

COOH 

:HOH 

CHOH 

CHOH 

CHOH 

:HOH 

CHOH 

CHOH 

CHOH 

]H2OH 

Erythrite 

CHO 

Erythrose 

COOH 

Erythronic 
acid 
(Trioxybutyric  acid) 

COOH 

Tartaric  acid 

The  Carbohydrates  295 

Pentose  (xylose,  arabinose,  etc.) 

CH2OH          CH2OH          CH2OH          COOH 

I  I  I 

(CHOH)3        (CHOH)3        (CHOH)3        (CHOH)3 

I  I  I  I 

CH2OH  CHO  COOH  COOH 

Pentite  Pentose  Pentonic  acid         Trioxyglutaric  acid 

Hexose  (glucose,  mannose,  galactose,  etc.) 

CH2OH  CH2OH  CH2OH          COOH 

I  I  I  I 

(CHOH)4        (CHOH)4        (CHOH)4        (CHOH)4 

I  I  I  I 

CH2OH  CHO  COOH  COOH 

Hexite  Hexose  Hexonic  acid        Tetraoxyadipic  acid 

Glycol  has  no  carbon  atom  possessing  asymmetry  and 
therefore  shows  no  optical  activity.  All  the  other  aldoses 
possess  one  or  more  asymmetric  carbon  atoms  and  there- 
fore exist  in  two  or  more  isomeric  forms.  Glycolaldehyde 
is  an  unstable  substance  and  has  never  been  isolated 
from  plant  or  animal  tissues.  The  same  is  true  of  glycer- 
aldehyde.  Both  of  these  are  known  through  the  syn- 
thetic products  only. 

A  tetrite,  inactive  erythrite  (i-erythrite)  is  found  free 
in  the  Alga,  Protococcus  vulgaris.  Tetroses  have  never 
been  found  in  nature,  but  have  been  prepared  syntheti- 
cally. There  are  theoretically  possible  twelve  isomeric 
aldopentoses,  viz.,  an  optically  inactive,  a  dextro-  and 
a  levorotatory  form  of  each  of  the  four  possible  aldo- 
pentoses, whose  formulae  are  illustrated  as  follows : 


296     Organic  Chemistry  for  Students  of  Medicine 

CH2OH    CH2OH     CH2OH     CH2OH 

I        I          I          I 
HO— C— H  H— C— OH   H— C— OH  HO-C— H 

I        I          I          I 
HO— C— H   H— C— OH  HO— C— H    H— C— OH 

I        I          I          I 
HO— C— H  H— C— OH   H— C-OH  HO— C— H 

I        I          I          I 
CHO     CHO       CHO       CHO 

(1)  l-ribose  (2)  d-ribose  (3)  1-xylose  (4)  d-xylose 

CH2OH     CH2OH     CH2OH     CH2OH 

I         I         I         I 
HO— C— H    H— C— OH  HO— C— H    H— C— OH 

I         I         I         I 
H— C— OH  HO— C— H  HO-€— H    H— C— OH 

I         I         I         I 
H— C— OH  HO— C— H    H— C— OH  HO— C— H 

I         I         I          I 
CHO      CHO      CHO      CHO 

(5)  1-lyxose  (6)  d-lyxose  (7)  1-arabinose  (8)  d-arabinose 

From  these  are  obtained  on  reducing  the  aldehyde 
groups  to  primary  alcohol  radicals,  the  following  alcohols, 
the  pentites. 

CH2OH  CH2OH  CH2OH  CH2OH 


:— OH  H— C— OH      H— C— OH  HO— C— H 

I  I  I  I 

H— C— OH  HO— C— H  HO— C— H  H— C— OH 

I  I  I  I 

H— C— OH  H— C— OH  HO— C— H  H— C— OH 

I  I  I  I 

CH2OH  CH2OH  CH2OH  CH2OH 

Adonite  Xylite  I-arabite  d-arabite 

(From  1-  and  d-  (From  1-  and  d-  (From  1-lyxose  (From  d-lyxose 

ribose)  xylose)  and  1-arabinose)  and  d-arabinose) 


The  Carbohydrates  297 

Adonite  and  xylite  are  optically  inactive  although  each  con- 
tains two  asymmetric  carbon  atoms.  The  central  carbon 
atom  in  the  pentose  loses  its  asymmetry  when  the  carbonyl 
group  is  changed  to  carbinol,  for  in  the  case  of  adonite  the 
two  groups  marked  off  by  the  dotted  lines  are  alike  and 
there  exists  accordingly  the  same  type  of  internal  com- 
pensation with  respect  to  influence  on  light,  as  was  seen 
in  mesotartaric  acid  (123). 

CH2OH  CH2QH 

H-C-OH  R  H-C-OH 

_______  I  _________  I  I 

H—  C—  OH     =  H—  C—  OH      H—  C—  OH 


H-C-OH 


CH2OH  CH2OH 

Adonite 

When  the  symmetry  of  the  molecule  is  destroyed  by 
oxidation  of  one  primary  alcohol  radical,  the  central  car- 
bon atom  again  becomes  asymmetric  and  optical  activity 
is  restored.  A  simple  test  as  to  whether  a  compound  is 
inactive  because  of  intramolecular  compensation,  is  to 
determine  whether  by  rotating  the  projection  formula 
180°  in  the  plane  of  the  paper  it  can  be  made  to  coincide 
with  the  projection  formula  of  its  mirror  image.  When- 
ever the  two  formulae  can  be  made  to  coincide,  the  mole- 
cules which  they  represent  are  identical  and  therefore  can- 
not be  optically  different.  1-arabinose  and  1-xylose  and 
possibly  d-ribose  occur  in  nature,  while  lyxose  does  not. 
152.  Determination  of  Structure. — We  may  now  in- 


298    Organic  Chemistry  for  Students  of  Medicine 

quire  in  what  way  it  is  possible  to  decide  which  of  the  sev- 
eral formulae  (1-8)  of  the  aldopentoses  is  to  be  assigned 
to  each  of  the  naturally  occurring  sugars.  If  the  pro- 
jection formula  for  each  one  of  the  four  pentoses  having 
different  configuration  can  be  determined,  the  other  four, 
being  their  mirror  images,  can  at  once  be  properly  named. 
If  the  four  forms  in  question  (page  296)  be  oxidized  at 
both  the  aldehyde  group  and  at  the  primary  alcohol  group 
there  will  result  for  each  pentose  form  a  trihydroxy 
glutaric  acid  of  similar  configuration. 

CH2OH     CH2OH     CH2OH     CH2OH 

HO— C— H  HO— C— H    H— C— OH  H— C— OH 

I         I          I         I 
HO— C— H  HO— C— H  HO— C— H  HO— C— H 

I         I          I         I 
HO— C— H   H— C— OH   H— C— OH  HO— C— H 

I         I          I         I 
CHO      CHO      CHO      CHO 


i   i   i 

COOH     COOH     C( 


COOH     COOH 
HO— C— H  HO— C— H    H— C— OH  H— C— OH 

HO— C— H  HO— C— H  HO— C— H  HO— C— H 

i         I          I         I 
HO— C— H    H— C— OH  H— C— OH  HO— C— H 


:OOH         COOH          COOH        COOH 

(1)   Inactive  (2)   Active  (3)   Inactive  (4)   Active 

Two  of  these  will  be  active  and  two  inactive  because  on 
converting  both  end  carbon  atoms  into  similar  groups  (car- 


The  Carbohydrates  299 

boxyl),  the  central  carbon  atom  in  (1)  and  (3)  loses  its 
asymmetry  and  the  molecule  presents  internal  optical 
compensation  (151). 

Arabinose  and  ribose  yield  the  same  osazone,  so  their 
difference  in  configuration  must  lie  in  the  H  and  OH  on 
the  carbon  atom  next  to  the  aldehyde  group,  since  these 
only  are  displaced  in  osazone  formation  (p.  285).  The 
pairs  of  formulae  which  fulfill  this  condition  are  (1)  and 
(2)  or  (3)  and  (4)  (p.  298).  Arabinose  and  ribose  must 
be  represented  by  one  of  these  pairs. 

Arabinose  on  oxidation  yields  an  optically  active  trihy- 
droxy  glutaric  acid,  while  ribose  and  xylose  produce  in- 
active acids.  This  necessitates  assigning  the  formulse 
(1)  or  (3)  to  ribose  and  xylose,  and  arabinose  must  be 
either  (2)  or  (4).  Lyxose  must  then  be  whichever  of  the 
formulse  (2)  or  (4)  is  not  assigned  to  arabinose.  But  the 
fact  that  arabinose  and  ribose  yield  the  same  osazone 
shows  that  if  arabinose  is  (2)  ribose  must  be  (1),  or  if 
arabinose  is  (4)  ribose  must  be  (3). 

When  a  pentose  is  subjected  to  Kiliani's  reaction  (p.  290) 
the  resulting  hexose  will  present  two  different  configura- 
tions, since  when  the  hydroxyl  group  is  formed  in  the  cyan- 
hydrin  formation  there  is  just  as  great  a  chance  that  it  will 
take  up  its  position  on  one  side  as  another  (see  lactic 
acid,  66).  When  the  hexoses  derived  from  arabinose  or 
xylose  are  oxidized  to  dibasic  acids,  both  are  found  to  be 
active,  while  those  derived  from  lyxose  are  one  active  and 
the  other  inactive.  The  formulas  for  inactive  acids  must 
show  internal  compensation,  since  each  contains  two 
asymmetric  carbon  atoms. 


300     Organic  Chemistry  for  Students  of  Medicine 

CH2OH 

H— C— OH 

I  I 

HO— C— H  HO— C— H 


CH2OH 
HO— C— H 


H— C— OH 


HO— C— H 

CHO 


CH2OH 
HO— C— H 
HO-C-H 

H— C— OH 
HO— C— H 
CHO 


CH2OH 
HO— C— H 

HO— C— H 

I 
H— C— OH 

H— C— OH 
CHO 


i      i 


COOH 

HO— C— H 

I 
HO— C— H 

H— C— OH 
HO— C— H 
COOH 

Active  acid 


COOH 
HO-C— H 
HO— C— H 
H— C— OH 
H— C— OH 
COOH 

(2)    Active  acid 


CH2OH 
H— C— OH 
HO— C— H 
HO— C— H 

HO— C— H 

I 
CHO 

i 

COOH 
H— C— OH 
HO— C— H 
HO— C— H 
HO— C— H 

COOH 

Active  acid 


CH2OH 

I 
H— C— OH 

HO— C— H 

HO— C— H 

I 
H— C— OH 

I 
CHO 

i 

COOH 

H— C— OH 

I 
HO— C— H 

HO— C— H 
H— C— OH 


COOH 

(4)     Inactive  acid 


The  Carbohydrates  301 

It  follows,  therefore,  that  the  formula  of  arabinose  must 
be  (2),  and  ribose  which  yields  the  same  osazone  must  be 
(1),  and  lyxose,  being  the  only  pentose  from  which  hexoses 
are  derived  yielding  an  active  and  an  inactive  dicarboxy- 
lic  acid,  must  be  (4).  Xylose  must  then  be  represented 
by  (3),  the  only  one  remaining. 

THE  PENTOSES 

153.   The  structural  formulae  for  the  three  biologically 
important  pentoses  are  the  following : 

CH2OH       CH2OH       CH2OH 

I  1  I 

HO— C— H    HO— C— H      H— C— OH 

I  I  I 

HO— C— H    HO— C— H    HO— C— H 

I  I  I 

HO— C— H      H— C— OH    H— C— OH 

I  I  I 

CHO        CHO        CHO 

d-ribose  1-arabinose  1-xylose 

d-ribose  has  been  found  only  in  the  nucleic  acids.  Judg- 
ing from  the  amount  of  furfural  obtained  from  various 
tissues  when  these  are  distilled  with  acids,  the  human  body 
contains  about  10.5  grams  of  pentose.  1-arabinose  and 
1-xylose  are  apparently  not  found  in  nature  in  the  free 
state,  but  only  in  the  form  of  their  polysaccharides,  araban 
and  xylan  (162)  in  the  gums  and  woody  tissues  of  plants. 
The  pentoses  are  water-soluble  and  show  the  general 
properties  of  alcohols  and  aldehydes.  1-arabinose  is 
obtained  from  the  hydrolysis  of  gum  arabic,  peach  gum, 
cherry  gum,  etc.  It  crystallizes  in  prisms  and  has  a  sweet 


302     Organic  Chemistry  for  Students  of  Medicine 

taste.  It  is  dextrorotatory,  its  designation  1-arabinose 
being  due  to  its  stereochemical  relationship  to  glucose 
(155).  It  melts  at  160°. 

1-xylose  is  formed  by  hydrolysis  of  xylan,  which  is 
found  to  the  extent  of  17-25  %  in  the  straw  of  wheat, 
rye,  and  other  cereal  grains.  It  crystallizes  in  doubly 
refractive  prisms  which  melt  at  144-145°. 

In  marked  contrast  to  the  more  common  hexoses,  the 
pentoses  are  incapable  of  oxidation  in  the  animal  body 
except  to  a  very  slight  extent.  After  the  administration 
of  even  small  doses  by  mouth  they  appear  in  the  urine. 
In  the  case  of  certain  individuals,  there  is  excreted  regu- 
larly in  the  urine,  regardless  of  the  character  of  the  diet,  a 
considerable  amount  of  a  pentose  which  has  not  been  iden- 
tified with  certainty,  but  is  probably  arabinose  or  ribose. 
As  much  as  36  grams  per  day  has  been  reported  in  the 
urines  of  such  persons.  This  chronic  pentosuria  appears 
to  be  without  ill  effects,  and  is  apparently  hereditary. 

Temporary  pentosuria  frequently  follows  the  ingestion 
of  fruits  and  berries,  many  of  which  contain  pentoses  or 
soluble  pentosans. 

Reactions  of  Pentoses.  —  The  reaction  for  the  estima- 
tion of  the  pentoses  or  their  polysaccharides  depends  upon 
the  ready  formation  of  furfural  on  treatment  with  mineral 
acids.  The  furfural  produced  is  distilled  off  with  steam 
and  is  precipitated  with  phloroglucinol  (194).  The  latter 
is  a  cyclic  trialcohol  compound  with  which  furfural  forms 
a  very  insoluble  compound  on  condensation.  From  the 
weight  of  furfural  phloroglucide  the  pentose  content  of  the 
sample  is  estimated.  Barbituric  acid  (139)  by  virtue  of  its 


The  Carbohydrates  303 

hydroxyl  group  likewise  condenses  with  furfural  to  form  a 
very  insoluble  product,  which  has  been  made  the  basis  of 
a  quantitative  estimation  of  the  pentoses. 

With  certain  other  cyclic  polyalcohols  the  pentoses  in 
acid  solution  give  characteristic  color  reactions.  Most 
important  is  the  colored  derivative  with  orcin  (196). 

154.  Methyl  Pentoses.  —  There  is  found  in  nature  a 
class  of  compounds  called  glucosides  (161)  which  contain 
a  hexose,  a  disaccharide,  or  a  methyl  pentose  in  union  with 
some    other    substance.     The    second    substances    vary 
greatly  in  their  chemical  character,  but  in  most  instances 
they  are  alcohols.     They  are  found  in  seeds,  roots,  leaves 
and  bark  of  plants,  and  are  broken  up  by  acids  or  by  spe- 
cific enzymes,  but  not  by  alkalies,  into  their  constitutents. 
Among  these  glucosides  quercitrin,  xanthorhamnin  and 
certain  of  the  saponins  (161)  yield  the  methyl  pentose 
rhamnose.    This  sugar  is  still  occasionally  referred  to  as 
isodulcite,  a  name  which  it  once  held  owing  to  the  mis- 
taken belief  that  it  was  a  hexahydric  alcohol.     Its  for- 
mula is 

CH3— CHOH— CHOH— .CHOH— CHOH— CHO 

Rhamnose  is  crystalline,  the  crystals  containing  one 
molecule  of  water.  It  melts  at  93°. 

Other  methyl  pentoses  found  in  nature  are'fwose  in  the 
form  of  the  polysaccharide  fucosan  in  certain  seaweeds, 
and  chinowse  in  the  form  of  the  glucoside  chinovin  found 
especially  in  cinchona  bark. 

155.  The  Hexoses.  —  There  are  sixteen  possible  stereo- 
chemical    isomers    of    the    sugars    having   the   formula 


304     Organic  Chemistry  for  Students  of  Medicine 

CH2OH— (CHOH)4— CHO.  These  represent  eight  forms 
and  their  mirror  images.  Of  the  eight  pairs  of  sugars 
possible,  two  pairs  are  unknown,  so  that  but  six  need  be 
considered.  Their  structural  formulae  are  arrived  at 
through  their  relation  to  the  pentoses  and  the  optical  prop- 
erties of  the  dibasic  acids  which  they  yield  on  oxidation. 
When  Kiliani's  reaction  (151)  is  applied  to  arabinose, 
there  are  obtained  on  reducing  the  resulting  lactone  two 
aldohexoses  which  are  very  common  in  nature,  viz., 
glucose  and  mannose.  It  has  been  pointed  out  in  describ- 
ing the  synthesis  of  hexoses  from  pentoses  that  the  only 
difference  possible  must  be  due  to  the  difference  in  position 
of  the  hydroxyl  group  on  the  carbon  atom  adjoining  the 
aldehyde  group.  Glucose  and  mannose  must  be  repre- 
sented by  the  following  two  structures,  A  and  B :  — 

CH2OH  CH2OH  CH2OH 

I  I  I 

HO— C— H       HO— C— H  HO— C— H 

I  I  I 

HO— C— H  <-  HO— C— H      ->    HO— C— H 

I  I  I 

H— C— OH       H— C— OH  H— C— OH 

I  I  I 

H— C— OH  CHO  HO— C— H 

I  I 

CHO  CHO 

A  Arabinose  B 

When  glucose  is  oxidized,  it  yields  a  dibasic  acid  called 
saccharic  acid  (p.  313).  One  of  the  hexoses  not  found  in 
nature,  but  obtained  by  Fischer  by  synthesis,  viz.  gulose, 
also  yields  on  oxidation  saccharic  acid.  This  being  the 


The  Carbohydrates  305 

case,  the  arrangement  of  the  H  and  OH  groups  on  all  the 
four  central  carbon  atoms  must  be  alike  in  glucose  and 
gulose,  for  these  carbon  atoms  and  their  H  and  OH 
groups  are  not  affected  in  any  way  by  transforming  the 
sugar  into  saccharic  acid.  It  follows  that  the  difference 
between  glucose  and  gulose  must  be  explainable  as  the  re- 
sult of  the  asymmetry  due  to  the  difference  in  position  of 
the  aldehyde  and  primary  alcohol  groups  with  respect  to 
the  peculiar  arrangement  of  the  rest  of  the  molecule.  It 
also  follows  that  any  formula  which  is  the  same  when 
the  CHO  and  CH2OH  groups  are  transposed  cannot 
represent  glucose  and  gulose,  for  such  a  formula  could  not 
represent  two  different  sugars.  In  the  following  formulae 
C  fulfills  the  last  condition,  while  D,  on  transposing  the 
end  groups,  leads  to  a  different  sugar. 

CH2OH     CHO      CH2OH     CHO 

I         I         I          I 
HO— C— H  HO— C— H  HO— C— H   HO— C— H 

I         I         I         I 
HO— C— H  HO— C— H  HO— C— H  HO— C— H 

I    -»    I         I    ->    I 
H— C— OH  H— C— OH  H— C— OH  H— C— OH 

H— C— OH  H— C— OH  HO— C— H   HO— C— H 

I  I  I  I 

CHO  CH2OH  CHO  CH2OH 

C  D 

Same  sugar  after  transposing  Different  sugar  after  transposing 

terminal  groups  terminal  groups 

Glucose  is  therefore  represented  by  the  formula  D  and 
mannose  is  C.  The  formula  F  must  accordingly  represent 
gulose. 


306     Organic  Chemistry  for  Students  of  Medicine 

CH2OH  CH2OH 

I  I 

H— C— OH          H— C— OH 

I  I 

HO— C— H  HO— C— H 

I  I 

H— C— OH  H— C— OH 

H— C— OH         HO— C— H 

I  I 

CHO  CHO 

F  G 

Idose,  another  sugar  not  found  in  nature  but  ob- 
tained synthetically,  yields  the  same  osazone  as  gulose, 
and  their  difference  in  structure  rests  therefore  in  the 
positions  of  the  H  and  OH  adjacent  to  the  aldehyde 
group,  since  only  these  two  are  affected  in  osazone 
formation.  This  is  further  supported  by  the  fact  that 
xylose  when  subjected  to  Kiliani's  reaction  yields  a 
mixture  of  gulose  and  idose.  It  has  been  already  shown 
that  gulose  is  represented  by  F,  so  idose  must  have  the 
structure  G. 

d-galactose  is  a  naturally  occurring  sugar.  On  reduc- 
tion it  yields  an  inactive  hexahydric  alcohol  and  on  oxida- 
tion an  inactive  dibasic  acid.  When  converted  by  Kiliani's 
reaction  into  two  heptonic  acids  and  on  further  oxidation 
of  the  latter  into  pentahydroxy  pimelic  acids,  both  prod- 
ucts are  optically  active.  From  considerations  anal- 
ogous to  those  described  in  arriving  at  the  structures 
of  other  hexoses,  the  formula  ascribed  to  galactose  is  the 
following : 


The  Carbohydrates  307 

CH2OH 

I 
HO— C— H 

H— C— OH 
H— C— OH 
HO— C— H 
CHO 

156.  The  Ketoses.  —  There  are  found  in  nature  but 
two  representatives  of  the  ketohexoses,  viz.  fructose  and 
sorbose.  The  latter  is  very  rare,  but  the  former  is  one  of 
the  very  widespread  and  important  sugars. 

d-fructose  is  found  together  with  glucose  in  sweet  fruits 
and  is  chemically  combined  with  it  in  cane  sugar,  with 
glucose  and  galactose  in  raffinose,  a  trisaccharide  found 
in  cotton  seed,  with  mannose  as  mannotetrose  found  in 
manna,  and  with  galactose  in  lupeose,  a  tetrose  found 
in  the  seeds  of  the  lupine.  There  is  a  starch-like  polysac- 
charide,  inulin,  in  the  tubers  of  the  dahlia,  which  yields 
fructose  on  hydrolysis. 

d-fructose  is  found  in  nature.  It  is  levorotatory,  not- 
withstanding its  designation  as  d-fructose.  Fischer  de- 
signated as  the  d-,  1-,  or  i-  form  all  monoses  which  are 
derived  from  a  d-,  1-,  or  i-hexose  respectively,  d-fructose 
can  be  derived  from  d-glucose,  hence  its  name.  The  letter 
denoting  the  form  of  a  monose  signifies  to  what  optical 
form  of  hexose  the  monose  is  related,  and  not  the  direction 
of  its  rotation  of  the  plane  of  polarized  light. 


308     Organic  Chemistry  for  Students  of  Medicine 

It  is  distinctly  sweeter  than  any  other  sugar,  and  is  more 
unstable  than  the  aldohexoses.  The  constitution  as- 
signed to  it  is : 

CH2OH 

HO— C— H 
HO— C— H 

H— C— OH 

I 

c=o 

CH2OH 

On  oxidation  it  yields  formic,  glycolic,  tartaric,  and  tri- 
hydroxy  glutaric  acids. 

CH2OH  COOH 

I  I 

HO-C— H  HO-C— H 

| 

HO— C— H         ll2  HO— C— H 

I  I 

H— C— OH  H— C— OH 

=0  COOH 


v^ 

i 

CH 


;OH  HCOOH 

Trihydroxy  glutaric  and 
formic  acids 


Since  the  cleavage  may  take  place  on  one  side  of  the 
carbonyl  group  as  well  as  on  the  other,  this  group  of  oxi- 
dation products  shows  that  the  carbonyl  group  is  but  one 
removed  from  the  terminal  carbon  atom. 


The  Carbohydrates 


309 


CH2OH 

I 
HO—  C—  H 

I 
HO—  C—  H 

I 
H—  C—  OH 

--I- 
C=0 

I 
CH2OH 


COOH 

I 
HO—  C—  H 

I 
HO—  C—  H 

I 
COOH 

COOH 


CH2OH 

Glycolic  and 
tartaric  acids 


Whereas  the  aldopentoses  and  aldohexoses  yield  normal 
carbon  chain  derivatives  when  subjected  to  the  cyanhy- 
drin  synthesis  (page  287),  fructose  yields  an  acid  with 
the  following  structure  : 


CH2OH 

CH2OH 

( 

:H2OH 

HO—  C—  H 

1 

HO—  C—  H 

1 

HO—  ( 

:—  H 

HO—  C—  H 

1 

HO—  C—  H 

1 

HO—  ( 

:—  H 

.. 

H—  C—  OH 
C=0    i 
CH2OH 

Fructose 

H—  C—  OH 
-HCN    i/OH 

|XCN 
CH2OH 

Cyanhydrin 

H—  ( 

He 

:—  OH 

/OH 

—  ( 

]H2OH 

ptonic  acid 

OOH 


This  harmonizes  with  the  assumption  that  the  structure 
assigned  to  fructose  is  correct,  for  the  ketone  structure  of 
fructose  must  necessarily  lead  to  the  formation  of  a 
branched  carbon  chain. 


310     Organic  Chemistry  for  Students  of  Medicine 

This  heptonic  acid  when  reduced  by  heating  with  hydri- 
odic  acid  (149)  is  changed  into  methyl-n-butyl  acetic  acid 

CHs CHs CH2 CIl2\ 

>CH— COOH 
CH/ 

which   has   been   synthesized    by   the    Claisen    reaction 
(127). 

The  same  osazone  is  obtained  from  d-fructose  as  from 
d-glucose.  It  is  therefore  evident  that  the  configuration 
of  the  molecules  of  these  hexoses  differ  only  in  the  ketone 
group  and  its  adjacent  terminal  carbon  atom.  The 
identity  of  the  osazones  serves  to  confirm  the  idea  that  in 
glucose  the  a-carbon  atom  and  in  fructose  the  terminal 
carbon  atom  react  with  a  second  molecule  of  phenyl- 
hydrazine  after  hydrazone  formation  has  taken  place.  In 
other  words,  it  is  definite  evidence  that  in  the  osazones  the 
two  phenylhydrazine  groups  are  united  to  adjacent  carbon 
atoms.  The  osazone  from  these  two  sugars,  which  may 
properly  be  called  glucosazone  or  fructosazone,  has  the  fol- 
lowing constitution : 

CH2OH 

(CHOH)3 

C=N— NH— C6H5 

I 
CH=N— NH— C6H5 

Glucose  may  be  converted  into  fructose  by  warming  the 
osazone  with  hydrochloric  acid.  The  two  phenylhydra- 
zine groups  are  separated  by  hydrolysis  and  there  results 


The  Carbohydrates  311 

an  osone,  a  compound  containing  an  aldehyde  and  a  ketone 
group : 

CH2OH  CH2OH 

I  I 

(CHOH)3  (CHOH)3 

C=N— NHC6H5       HOH         C=O    H2N— NH— C6H5 

I  +  ->    I       + 

CH=N— NHC6H5    HOH        CHO    H2N— NH— C6H5 

Osazone  Osone  Phenylhydrazine 

On  careful  reduction  the  aldehyde  group  is  reduced 
to  a  primary  alcohol  and  fructose  is  formed.  This 
reaction  is  general  for  the  conversion  of  aldoses  into 
ketoses. 

In  harmony  with  what  has  been  said  regarding  which 
two  carbon  atoms  react  in  the  formation  of  the  osazones, 
it  is  found  that  while  d-glucose  and  d-mannose  yield 
different  hydrazones  they  yield  the  same  osazone.  It  has 
been  shown  already  that  the  molecules  of  these  sugars 
differ  only  in  the  positions  occupied  by  the  H  and  OH 
linked  to  the  a-carbon  atom  (152). 

Heptoses,  octoses,  and  nonoses,  aldoses  containing 
seven,  eight,  and  nine  'carbon  atoms,  have  been  prepared 
by  Fischer  from  the  hexoses  by  the  cyanhydrin  synthesis. 
These  compounds  are  not  found  in  nature.  It  is  of 
biological  interest  that  they  are  not  fermentable  by 
yeast. 

157.  Special  Properties  of  the  Hexoses.  —  Among  the 
many  possible  aldo-  and  keto-hexoses,  there  are  only  four 
which  are  of  great  importance  as  natural  products : 


v^j.a.^vyj 

HO— C— H 


312     Organic  Chemistry  for  Students  of  Medicine 

CH2OH  CH2OH  CH2OH  CH2OH 

I  I  I 

HO— C— H     HO— C— H     HO— C— H 

I  I  I 

HO— C— H     HO— C— H     HO— C— H        H— C— OH 

I  I  I  I 

H— C— OH     H— C— OH     H— C— OH      H— C— OH 

I  I  I 

H— C— OH  HO— C— H  C=O      HO— C— H 

I  I  I 

CHO  CHO  CH2OH  CHO 

d-mannose  d-glucose  d-fructose  d-galactose 

Mannose  is  seldom  found  in  nature  as  such  and  only 
in  small  amounts.  It  forms  in  plants  a  cellulose-like  sub- 
stance, mannocellulose  (mannan),  in  the  cell  walls,  and  in 
this  form  occurs  in  large  quantities,  an  especially  good 
source  being  the  ivory  nut.  Mannose  is  obtained  as  a 
hard,  solid  amorphous  mass  which  is  deliquescent  and 
dissolves  easily  in  water,  slightly  in  alcohol  and  is  insoluble 
in  ether.  It  is  identified  as  the  phenylhydrazone  which 
melts  at  195-200°. 

On  reduction  with  nascent  hydrogen  mannose  is  con- 
verted into  the  hexahydric  alcohol,  mannite.  The  latter 
is  found  in  considerable  amounts  in  manna,  that  from  the 
ash  containing  30-60  %.  Mannose  is  easily  fermentable 
by  yeast.  It  is  crystalline  and  melts  at  132°. 

d-glucose  (dextrose,  grape  sugar)  is  found  widely  dis- 
tributed with  fructose  in  ripe  fruits  and  other  parts  of 
plants,  including  the  nectar  of  flowers.  It  is  formed 
from  the  hydrolysis  of  cane  sugar,  malt  sugar,  and  milk 
sugar,  starch,  etc.  It  is  the  sugar  which  is  a  normal  con- 
stituent of  the  blood  and  lymph,  being  present  to  1  part 


The  Carbohydrates  313 

in  1000.  In  diabetes,  a  disease  of  the  pancreas,  it  occurs 
in  the  urine  sometimes  in  large  amounts. 

On  reduction  of  glucose  the  hexahydric  alcohol  d-sorbite 
is  formed,  and  on  oxidation  gluconic  acid,  analogous  to 
mannonic  acid,  and  on  further  oxidation  the  dibasic 
saccharic  acid,  analogous  to  manno-saccharic  acid. 

d-glucose  crystallizes  from  alcohol  in  water-free  form, 
and  from  water  as  a  hydrate,  CeH^Oe  +  HzO.  Water- 
free  glucose  melts  at  146°  and  at  170°  loses  water  from  its 
H  and  OH  groups,  several  molecules  of  glucose  condensing 
to  a  polysaccharide  glucosan.  By  treating  glucose  with 
dehydrating  agents,  such  as  strong  acids,  several  molecules 
are  condensed  to  form  polysaccharides,  complexes  having 
a  high  molecular  weight. 

On  oxidation  of  d-glucose  the  aldehyde  group  is  first 
attacked  and  is  converted  into  gluconic  acid,  and  on  further 
oxidation  the  primary  alcohol  group  is  converted  succes- 
sively into  an  aldehyde  and  then  into  a  carboxyl  group : 

CH2OH      CH2OH      CHO       COOH 
(CHOH)4  +O  (CHOH)4  +0  (CHOH)4  +Q  (CHOH)4 


COOH      COOH      C( 


CHO       COOH      COOH      COOH 

d-glucose  d-gluconic  acid  d-glycuronic  acid  Saccharic  acid 

Although  this  is  the  course  of  the  oxidation  of  glucose 
in  the  laboratory,  and  although  animals  regularly  oxidize 
large  amounts  of  glucose,  these  acids  do  not  represent  the 
course  of  the  first  steps  in  the  destruction  of  sugar  by  the 
living  organism.  Instead  the  glucose  molecule  is  disso- 
ciated into  simpler  compounds  containing  but  three  and 


314    Organic  Chemistry  for  Students  of  Medicine 

two  carbon  atoms,  and  it  is  these  which  are  oxidized.  The 
first  step  in  the  biological  degradation  of  the  sugars  is 
therefore  not  oxidative  but  hydrolytic  (164). 

d-glucose  is  the  most  easily  utilized  of  the  hexoses.  In 
healthy  persons  the  capacity  to  utilize  this  sugar  is  as 
great  as  the  capacity  of  the  digestive  tract  to  absorb  it. 
Healthy  young  men  have  been  known  to  absorb  more  than 
a  pound  of  glucose  within  twenty-four  hours  without  the 
appearance  of  sugar  in  the  urine.  It  is  likewise  easily 
fermented  by  yeasts,  in  which  process  it  is  converted  into 
alcohol  and  carbon  dioxide  (see  fermentation). 

ACTION   OF   ALKALIES   ON   GLUCOSE 

When  allowed  to  stand  for  several  months  with  dilute 
alkali  glucose  is  converted  to  the  extent  of  50-60%  into 
inactive  lactic  acid,  .5-2  %  into  formic  acid,  and  30-50  % 
into  several  hydroxy  acids.  Among  other  cleavage  prod- 
ucts formed  by  alkalies  is  methyl  glyoxal,  the  aldehyde  of 
pyruvic  acid. 

A  reaction  of  biological  interest  is  the  formation  of 
methyl  imidazole  by  the  action  of  ammonia  and  zinc 
hydroxide  on  glucose.  This  illustrates  in  a  suggestive 
way  the  possibility  of  the  formation  of  certain  cyclic 
compounds  within  the  animal  body  through  the  participa- 
tion of  carbohydrate.  It  will  be  recalled  that  one  of  the 
amino  acids,  histidine  (138),  derived  from  proteins,  contains 
the  imidazole  ring.  The  formation  of  methyl  imidazole 
from  glucose  and  ammonia  is  best  explained  as  the  result 
of  the  interaction  of  ammonia  with  the  dissociation  pro- 
ducts of  glucose,  methyl  glyoxal,  and  formaldehyde : 


The  Carbohydrates 


315 


Formaldehyde 

Methyl  glyoxal    Ammonia  /^TT        /"»       TVTTT 

L^-tl3 — L- — IN  ±iv 

>CH+3H2O 
CH— N^ 

Methyl  imidazole 

In  solution  in  water  containing  the  slightest  trace  of 
alkali  (OH  ions),  glucose  is  in  part  transformed  into  d- 
fructose  and  d-mannose.  The  explanation  of  this  change, 
first  studied  by  de  Bruyn  and  van  Eckenstein  is  as  follows : 

The  aldose  d-glucose,  in  water  solution  passes  to  some 
extent  into  the  forms  illustrated  by  the  following  structural 
formulae : 


CH2OH 

I 
(CHOH)3 

and 


CHjOH 

1 

CH2OH 

1 

(CHOH)3 
1 

(CHOH)3 
>       1 

CHOH 

CH* 

1 

>o 

CHO 

CH< 
>/\i" 

d-glucose 

(Jn 

Labile  tra 

CH2OH         CH2OH 


(CHOH)3       (CHOH)3 
I  or     | 

CHOH          CO 


CHO  CH2OH 

d-glucose  or  d-mannose        d-fructose 


316     Organic  Chemistry  for  Students  of  Medicine 

The  change  is  believed  to  take  place  through  the  lability 
of  one  hydrogen  atom  marked  X  in  the  intermediate  forms 
whereby  it  can  wander  from  one  to  the  other  of  the  two 
neighboring  carbon  atoms.  By  the  shifting  of  a  hydrogen 
from  the  end  carbon  atom  to  the  second  an  aldose  would  be 
regenerated,  but  by  the  law  of  chance  the  hydroxyl  group 
would  take  its  place  on  one  side  of  the  chain  as  frequently 
as  the  other,  and  d-glucose  would  be  regenerated  or  d-man- 
nose  would  be  formed  accordingly.  By  a  shifting  of  the 
hydrogen  atom  from  the  second  to  the  end  carbon  atom 
a  ketone  sugar  d-fructose  would  result.  When  therefore 
any  one  of  the  three  sugars  d-glucose,  d-mannose,  or  d- 
fructose  is  in  solution  in  the  presence  of  a  low  concentra- 
tion of  hydroxyl  ions,  it  will  pass  in  part  into  the  other 
two,  until  a  certain  proportion  exists  among  the  three 
kinds  of  molecules,  i.e.  each  form  is  in  dynamic  equilib- 
rium with  the  other  two.  If  by  some  means  the  glucose 
is  removed  from  the  system,  more  will  be  formed. 

This  observation  is  of  the  greatest  importance  in  that 
it  enables  us  to  understand  how  an  animal  may  absorb 
from  the  digestive  tract  mannose  or  fructose  and  yet  these 
never  be  present  in  the  blood.  They  are  always  trans- 
formed into  d-glucose  if  the  absorption  is  not  too  rapid,  in 
which  case  the  fructose  and  mannose  are  said  to  exceed 
the  assimilation  limit  since  they  escape  into  the  urine. 

d-glucose  yields  a  phenylhydrazone  which  melts  at 
144-146°,  and  an  osazone  which  melts  at  206°.  On  reduc- 
tion it  yields  the  hexahydroxy  alcohol  d-sorbite. 

d-fructose  is  actually  levorotatory,  but  is  called  the 
dextro  form  because  of  its  structural  relationship  to  d- 


The  Carbohydrates  317 

glucose.  Although  d-fructose  yields  the  same  osazone  as 
do  d-glucose  and  d-mannose,  it  is  easily  distinguishable 
from  these  by  its  peculiar  behavior  with  methyl  phenyl- 
hydrazine : 

C6H5— N— NH2 

CH3 

With  this  methyl-substituted  phenylhydrazine  d-fruc- 
tose and  other  ketoses  yield  osazones.  The  aldoses,  on  the 
other  hand,  do  not  react  with  this  reagent  beyond  the 
hydrazone  stage  under  ordinary  conditions.  The  methyl 
phenylosazone  of  fructose  melts  at  158-160°. 

The  capacity  of  the  animal  organism  to  utilize  fructose 
is  much  less  than  for  d-glucose.  d-fructose  is  easily  fer- 
mentable by  yeast. 

An  extremely  interesting  observation  is  the  formation 
of  d-fructose  from  d-mannite  by  a  kind  of  fermentation 
induced  by  Bacterium  'xylinum  Brown,  through  which 
the  alcohol  is  oxidized  to  a  ketone. 

d-galactose  is  present  in  milk  sugar  in  union  with 
d-glucose.  It  also  occurs  in  certain  polysaccharides,  as 
agar-agar,  and  in  certain  glucosides.  It  exists  in  the  brain 
in  considerable  amount  in  union  with  a  fatty  acid  and  a 
base  of  unknown  chemical  nature.  The  hexose  itself  has 
never  been  found  in  the  free  state  in  either  plants  or 
animals.  Galactose  is  easily  distinguishable  from  the 
other  hexoses  by  the  insolubility  in  dilute  nitric  acid  of 
the  dicarboxy  acid,  mucic  acid,  which  results  on  oxidation 
of  the  sugar  with  nitric  acid.  Mucic  acid  is  so  insoluble 
and  is  formed  so  nearly  quantitatively  that  its  formation 


318     Organic  Chemistry  for  Students  of  Medicine 

serves  as  the  best  available  method  of  estimating  galactose 
or  galactose-yielding  polysaccharides. 

d-galactose  is  much  less  readily  utilized  in  the  animal 
body  than  is  either  glucose  or  fructose,  and  on  the  inges- 
tion  of  even  moderate  amounts  is  eliminated  in  part 
unchanged  in  the  urine. 

158.  The  Disaccharides.  —  There  are  three  sugars  of 
great  biological  interest  which  yield  on  hydrolysis  two 
molecules  of  hexose.  The  molecular  weights  of  all  of 
them  correspond  to  the  formula  C^IfeOn.  They  are 
sucrose,  or  cane  sugar,  which  yields  on  hydrolysis  one  mole- 
cule of  d-glucose  and  one  of  d-fructose ;  maltose,  or  malt 
sugar,  which  yields  two  molecules  of  d-glucose  ;  and  lactose, 
or  milk  sugar,  which  yields  one  molecule  of  d-galactose 
and  one  of  d-glucose. 

Sucrose,  C^H^On,  occurs  in  the  juices  of  many  plants, 
especially  sugar  cane  and  sugar  beet.  As  much  as  16-20  % 
of  the  dry  substance  of  the  plant  is  sucrose.  It  crystallizes 
readily.  The  sugar  is  extracted  from  the  finely  rasped 
beets  with  warm  water  and  the  solution  treated  with  lime, 
which  causes  the  neutralization  of  acids  in  the  juice,  and 
is  then  boiled  to  coagulate  the  proteins.  The  solution  is 
then  treated  with  carbon  dioxide  to  precipitate  most  of  the 
calcium,  and  after  this  with  sulphur  dioxide  whose  reducing 
action  discharges  the  color.  It  is  again  boiled  and  filtered, 
and  the  filtrate  evaporated  under  diminished  pressure  to 
crystallization.  The  mother  liquor  from  the  crystals  is 
molasses.  The  molasses  yields  another  portion  of  sucrose 
on  treatment  with  lime  or  strontium  hydroxide,  an  insol- 
uble calcium  or  strontium  saccharate  being  formed.  The 


The  Carbohydrates  319 

latter  is  decomposed  by  carbon  dioxide  and  the  liquid, 
freed  from  solid  calcium  or  strontium  carbonate,  yields  a 
crop  of  crystals  of  sugar.  The  molasses,  which  contains 
much  glucose,  is  in  great  part  fermented  for  the  preparation 
of  rum  or  alcohol  for  industrial  purposes. 

Sucrose  forms  large  monoclinic  crystals  which  are 
easily  soluble  in  water  and  melt  at  160°,  then  solidify 
to  a  glassy  mass  and  on  further  heating  become  brown 
with  the  formation  of  caramel.  The  specific  rotation  of 
cane  sugar  is,  for  a  solution  of  about  25  %  strength : 

[ak=+66.5° 

The  rotatory  power  is  made  use  of  in  the  estimation  of 
sucrose.  On  boiling  with  dilute  acids,  it  is  converted 
into  d-glucose  and  d-fructose.  The  resulting  solution 
rotates  the  plane  of  polarized  light  to  the  left,  since  the 
levorotatory  power  of  fructose  is  [a]D  =  —  93°  while 
for  d-glucose  or  dextrose  [a]D  =  +52.7°.  Since  the  direc- 
tion of  rotation  changes  when  cane  sugar  is  hydrolyzed, 
the  process  is  called  inversion,  and  the  product  invert 
sugar. 

The  same  conversion  of  sucrose  into  glucose  and  fructose 
is  brought  about  by  an  enzyme  invertase,  which  is  present 
in  yeast  and  in  the  mucous  membrane  of  the  small  intes- 
tine. The  rate  of  inversion  of  cane  sugar  by  acids  has 
been  very  carefully  studied,  and  it  has  been  found  that 
it  is  proportional  to  the  concentration  of  the  hydrogen  ions 
present.  The  hydrogen  ion  is  therefore  the  catalytic 
agent  for  this  hydrolytic  reaction. 

Sucrose  does  not  reduce  the  oxides  of  the  heavy  metals 


320     Organic  Chemistry  for  Students  of  Medicine 

(e.g.  Fehling's  solution)  as  do  glucose,  fructose,  mannose, 
and  the  other  aldoses  and  ketoses,  nor  does  it  form  com- 
pounds with  hydrazines.  It  does  not  therefore  contain  a 
carbonyl  (aldehyde  or  ketone)  group,  but  on  hydrolysis  to 
glucose  and  fructose  an  aldehyde  and  a  ketone  group  are 
formed.  It  contains,  however,  eight  hydroxyl  groups, 
since  it  yields  an  octa-acetyl  derivative. 

Sucrose  is  regarded  as  a  glucoside  of  d-fructose  (161).  It 
cannot  be  utilized  directly  by  an  animal,  being  excreted 
in  the  urine  when  introduced  directly  into  the  blood.  In 
the  digestive  tract  it  is  hydrolyzed  into  glucose  and  fruc- 
tose before  absorption. 

Maltose,  C^IfeOii  +  H20,  is  found  in  small  amounts 
in  many  plants.  It  is  the  end  product  of  the  action  on 
starch  of  the  enzyme  amylase  of  the  saliva  of  the  omniv- 
orous animals,  including  man.  It  has  been  found  in  human 
urine  in  disease  of  the  pancreas,  but  in  the  normal  organ- 
ism maltose  is  readily  utilized  either  when  introduced 
into  the  alimentary  tract  or  directly  into  the  blood.  The 
blood  contains  an  enzyme  maltose  which  converts  maltose 
into  two  molecules  of  d-glucose.  This  change  is  likewise 
effected  by  heating  with  dilute  acids.  There  is  no  cor- 
responding enzyme  in  the  blood  or  tissues  for  the  hydroly- 
sis of  sucrose  or  lactose. 

Maltose  reduces  solutions  of  the  oxides  of  the  heavy 
metals,  which  indicates  that  it  contains  a  carbonyl  group. 
Maltosazone  melts  at  205°. 

Isomaltose  is  a  disaccharide  which  is  formed  by  the 
dehydrating  action  of  strong  hydrochloric  acid  on  a  con- 
centrated solution  of  glucose.  Its  osazone  melts  at  200° 


The  Carbohydrates  321 

and  is  more  soluble  in  water  than  is  maltosazone.  Its 
stereochemical  configuration  is  sufficiently  different  from 
maltose  to  make  it  non-fermentable  with  yeast.  The 
enzymes  of  yeast  do  not  hydrolyze  it  to  hexoses,  but  the 
enzyme  emulsin  found  in  the  almond  converts  it  into  two 
molecules  of  glucose. 

Lactose  or  Milk  Sugar,  C^H^On  +  H2O,  is  found  nowhere 
but  in  the  milk  of  animals.  It  contains  a  carbonyl  group, 
since  it  reduces  certain  oxides  of  the  heavy  metals.  Its 
osazone  melts  at  200°. 

In  the  animal  organism  lactose  behaves  as  does  cane 
sugar.  When  taken  into  the  alimentary  tract,  it  is  hydro- 
lyzed  by  the  enzyme  lactose  into  d-glucose  and  d-galactose 
before  being  absorbed ;  and  if  introduced  directly  into  the 
blood,  is  principally  excreted  unchanged  in  the  urine.  The 
lactose  of  the  milk  is  derived  from  d-glucose  and  not  from 
the  food. 

Melibiose  is  isomeric  with  lactose  and  yields  the  same 
hexoses  on  hydrolysis.  It  results  together  with  d-fructose 
from  the  action  of  dilute  acids  or  of  invertase  upon  the 
trisaccharide  raffinose.  Like  lactose,  it  is  a  reducing  sugar. 
It  resembles  lactose  in  being  hydrolyzed  by  emulsin,  but 
differs  from  it  in  not  being  cleaved  by  lactase. 

159.  The  Stereochemical  Configuration  of  the  Sugars 
Determines  their  Biological  Value.  — Of  the  sixteen  isomers 
of  the  aldohexoses  only  three  are  readily  utilized  by  the 
higher  animals,  and  of  these  three,  d-glucose,  d-fructose, 
and  d-mannose,  only  the  former  has  a  high  assimilation 
limit.  Galactose  is  utilized  with  more  difficulty  than  the 
three  first  named. 


322     Organic  Chemistry  for  Students  of  Medicine 

A  similar  relationship  holds  in  the  case  of  the  disaccha- 
rides.  Before  these  can  be  utilized  biologically  they  must 
be  converted  into  the  CG  sugars,  and  there  is  a  marked 
difference  in  the  extent  to  which  various  organisms  are 
prepared  with  the  specific  enzymes  necessary  for  their 
cleavage.  Thus  the  invertase  of  yeast,  but  not  the  malt- 
ase  and  lactase,  act  on  cane  sugar.  Invertase  and  lac- 
tase  do  not  cleave  maltose.  Emulsin  does  not  hydrolyze 
any  of  these  disaccharides.  Certain  of  the  molds  are 
provided  with  all  of  these  enzymes. 

The  limitations  of  the  digestive  tract  are  similar  to 
those  of  yeasts.  The  mucous  membrane  of  the  intestine 
in  all  animals  contains  invertase  and  maltase  and  usually 
lactase.  The  blood  contains  maltase,  but  no  invertase 
or  lactase. 

Yeasts  show  among  the  races  great  variation  in  their 
capacity  to  effect  the  hydrolysis  of  the  disaccharides. 
Thus,  the  yeast  which  induces  alcoholic  fermentation  of 
milk,  forming  kephir,  contains  lactase,  while  beer  yeast 
does  not.  The  latter,  however,  can  cleave  cane  sugar  and 
ferment  the  resulting  sugars.  Many  yeasts  contain  both 
invertase  and  maltase,  and  can  ferment  both  these  sugars, 
but  Saccharomyces  Marxianus  contains  only  invertase 
and  can  ferment  therefore  sucrose,  but  not  maltose. 
Saccharomyces  octosporus,  on  the  other  hand,  can  ferment 
maltose  but  not  sucrose,  and  Saccharomyces  apiculatus, 
which  is  capable  of  fermenting  d-glucose,  d-mannose, 
and  d-fructose,  contains  no  enzyme  for  the  hydrolysis 
of  any  of  the  disaccharides,  and  cannot  ferment  the 
latter. 


The  Carbohydrates  323 

160.  Raffinose,    Ci8H32Oi6— 5  H2O,    is   a    trisaccharide 
found  in  small  amount  in  the  sugar  beet  and  therefore  in 
considerable  amount  in  molasses.     It  is  especially  plenti- 
ful in  the  cotton  seed   (10  %)   and  is  a  constituent  of 
Eucalyptus  manna.     On  hydrolysis  with  dilute  acids  it  is 
first  converted  into  fructose  and  melibiose,  and  the  latter 
into  d-glucose  and  d-galactose.     Top   yeast   effects  the 
cleavage  of  raffinose  into  d-fructose  and  melibiose,  and 
bottom  yeasts  ferment  it  completely.     Emulsin  converts 
raffinose  into  galactose  and  cane  sugar. 

THE  GLUCOSIDES 

161.  In  a  manner  analogous  with  the  reaction  of  the 
aldehydes  with  alcohols  to  form  acetals  (32),  the  aldoses 
can  react  with  alcohols  to  form  the  glucosides.     Many  such 
compounds  occur  in  nature  in  plants,  these  usually  contain- 
ing an  aromatic  alcohol,  aldehyde,  or  acid,  but  also  other 
classes   of   compounds.     The  carbohydrate  group  is  in 
most  cases  glucose,  but  glucosides  are  also  known  which 
yield  galactose,  rhamnose,  and  disaccharides.     Tlie  leayes 
of  Indigofera  tinctoria  and  of  Isatis  tinctoria  contain  a 
glucoside  indican,  from  which  the  dye  indigo  results  by  a 
process  of  fermentation.     The  madder  root  contains  among 
other  glucosides  ruberythric  acid,  which  yields  the  red  dye 
alizerin.     The  leaves  of  Digitalis  purpurea  yield  the  glu- 
coside digitalin,  which  exerts  a  peculiar  action  on  cardiac 
muscle.    Willow  bark  contains  salicin,  from  which  salicylic 
acid  (209)  is  derived.     The  roots  of  fruit  trees,  as  apple, 
peach,  etc.,  yield  the  glucoside  phlorizin,  which  is  much  em- 
ployed in  inducing  an  experimental  glycosuria  in  animals 


324     Organic  Chemistry  for  Students  of  Medicine 

for  biochemical  studies.     The  roots   of   Spiraea  contain 
gaultherin,  mustard  seeds  yield  myrosin,  etc. 

One  of  the  best  known  of  the  glucosides  is  amygdalin, 
from  the  bitter  almond.  Solutions  of  amygdalin  do  not 
reduce  solutions  of  the  heavy  metals,  a  fact  which  is 
taken  to  indicate  that  there  is  no  free  aldehyde  group. 
After  hydrolysis  with  dilute  acids  the  presence  of  glucose 
can  be  detected  by  the  reduction  of  Fehling's  solution, 
and  by  the  formation  of  an  insoluble  osazone  (p.  286) 
which  melts  at  205°.  Benzaldehyde  can  be  detected  by  its 
odor,  and  HCN  by  its  precipitate  with  silver  nitrate.  It 
is  soluble  in  alcohol  and  can  be  crystallized  from  this 
solvent.  Emulsin,  an  enzyme  contained  in  the  almond, 
hydrolyses  amygdalin  into  benzaldehyde  (204),  hydro- 
cyanic acid,  and  two  glucose  molecules.  Water  extract  of 
beer  yeast  contains  an  enzyme  which  splits  off  hydro- 
lytically  but  one  molecule  of  glucose  and  leaves  the  com- 
bination benzaldehyde,  hydrocyanic  acid,  and  glucose, 
the  glucoside  of  mandelic  acid  nitrile  (206). 

CONSTITUTION   OF   THE   GLUCOSIDES 

The  best-known  synthetical  glucosides  are  those  from 
glucose  and  methyl  alcohol.  When  a  concentrated  solu- 
tion of  d-glucose  in  methyl  alcohol  is  treated  with  gaseous 
hydrochloric  acid,  there  result  two  compounds  known  as 
a-methyl  glucoside  and  /3-methyl  glucoside.  The  a-form 
is  dextrorotatory  and  is  soluble  in  200  parts  of  alcohol; 
while  the  0-form  is  levorotatory  and  is  soluble  in  66.7 
parts  of  alcohol  at  100°.  They  can  therefore  be  separated 
by  their  different  solubilities.  Maltase  hydrolyzes  the 


The  Carbohydrates 


325 


a-glucoside  but  not  the  /3-form,  while  emulsin  hydrolyzes 
the  jS-form  but  not  the  a-form.  The  natural  glucosides 
are  in  general  hydrolyzed  only  by  emulsin,  and  for  this 
reason  they  are  termed  /3-glucosides.  The  structural 
formulse  assigned  to  a-  and  /3-methyl  glucosides  are  as 
follows : 

CH2OH  CH2OH 


H— C— OH 
H— C 


H— C— OH 
H— C 


HO— C— H 


a-Methyl  glucoside 


H— C— OH 


CH30— C— H 

/3-Methyl  glucoside 


The  reasons  for  assigning  these  constitutional  formulse 
are  the  following : 

1.  Only  a  single  molecule  of  alcohol  reacts  with  one  of 
glucose,  with  the  elimination  of  a  molecule  of  water. 
One  of  the  secondary  alcohol  radicals  must  therefore  enter 
into  the  reaction.  This  is  in  all  probability  the  7-hy- 
droxyl  group,  since  this  is  the  one  which  reacts  in  the  forma- 
tion of  lactones  (125),  and  since  no  compounds  other  than 
those  containing  7-hydroxyl  groups  form  glucosides.  The 
ease  with  which  the  glucosides  are  decomposed  by  hy- 
drolysis argues  strongly  against  the  union  of  the  alcohol 
radical  directly  to  carbon,  and  for  the  assumption  of  link- 
age through  oxygen  as  in  the  ethers.  The  mechanism 
of  glucoside  formation  may  therefore  be  represented  thus : 


326     Organic  Chemistry  for  Students  of  Medicine 

CH2OH 
H— C— OH 


(7)     H— C— O[H 
)  HO— C— H 


H— C— OH 


H 

Glucose 


+H 


Methyl  alcohol 


CH2OH 
H— C— OH 


+H20 


Glucoside 

Mutarotation.  —  Freshly  prepared  solutions  of  glucose 
rotate  the  plane  of  polarized  light  nearly  twice  as  much 
as  they  do  after  standing  for  a  time.  If  the  water  is 
evaporated  and  the  sugar  crystallized  it  will,  on  again 
dissolving  it,  show  the  high  rotation  value.  There  must 


The  Carbohydrates 


327 


occur  a  reversible  change  during  evaporation.  It  is 
believed  that  the  change  in  rotatory  power  is  the  result 
of  the  interaction  of  a  molecule  of  water  with  one  of 
glucose,  analogous  to  methyl  alcohol  and  glucose,  with 
the  loss  of  a  molecule  of  water  and  the  formation  of 
a  structure  analogous  to  a  glucoside,  but  with  OH  in 
place  of  the  OCH3. 

Maltose  is  regarded  as  a  glucoside  of  glucose : 

CH2OH  CHO 


H— C— OH 
H— C— 0|F 
HO— C— H 
H— C— OH 


0 


H 

d-glucose 


H— C— OH 

I 
HO— C— H 

H— C— OH 
H— C— OH 


HO CH2 

d-glucose 


Maltose 


328     Organic  Chemistry  for  Students  of  Medicine 


Sucrose,  which  contains  no  carbonyl  group,  is  represented 

as : 

CH2OH 


H— C— OH 

I 
H—  C— 0|H^ 

I 
HO— C— H 

H— C— OH 


c=  fo 


H|— C— OH 

H— C— OH 

HO— C— OH 

0=C 

I 
HOH2C 


d-fructose 


H 

d-glucose 


CH2OH 


CH2OH 


Sucrose 


Emil  Fischer  has  suggested  the  comparison  of  the  spe- 
cific action  of  enzymic  action  in  the  hydrolysis  of  sugars 
and  other  compounds,  with  the  relationship  between  lock 
and  key.  The  stereochemical  structures  of  both  the 
enzyme  and  the  molecules  of  the  substrate  determine 
whether  they  can  interact.  This  specificity  of  ferment 


The  Carbohydrates  32$ 

action  is  of  the  greatest  significance  for  the  life  of  the 
animal  or  plant  cell. 

The  union  of  galactose  in  the  galactolipins  of  the  brain 
and  of  ribose  in  nucleic  acids  is  probably  of  the  nature  of 
glucosides. 

THE   POLYSACCHARIDES 

162.  Starch  (C6Hi0O5)n  (amylum)  is  a  non-crystalline 
carbohydrate  produced  by  plants  as  a  reserve  material.  It 
is  closely  related  to  cellulose  on  the  one  hand,  a  compound 
whose  peculiar  properties  fit  it  to  be  the  skeletal  tissue 
of  plants,  and  to  the  simple  hexoses  and  disaccharides  on 
the  other,  into  which  it  is  readily  converted  by  hydrolysis. 
Starch  is  insoluble  in  water  and  exists  in  grains,  tubers, 
fruits,  etc.,  in  the  form  of  grains.  These  consist  of  at 
least  two  kinds  of  carbohydrates :  granulose,  which  is 
colored  blue  by  iodine,  and  starch  cellulose,  which  is  not. 
The  blue  color  produced  by  iodine  is  discharged  on  heating 
but  reappears  on  cooling.  Starch  has  a  very  high  molec- 
ular weight  (32,000)  and  when  boiled  with  water  under- 
goes incipient  hydrolysis  and  is  changed  into  soluble  starch. 
The  latter  forms  an  opalescent  colloidal  solution. 

The  amylase  of  the  saliva  of  certain  animals  rapidly 
causes  hydrolysis  of  starch  into  a  series  of  simpler  car- 
bohydrates, the  dextrines,  the  final  product  being  maltose. 
Acid  hydrolysis  converts  starch  into  d-glucose. 

The  form  and  appearance  of  the  starch  grains  vary 
with  their  origin.  It  is  a  simple  matter  for  one  familiar 
with  the  forms  to  identify  by  microscopical  methods  the 
source  of  the  starch. 

Starch  is  not  the  first  product  of  the  synthetic  activity 


330     Organic  Chemistry  for  Students  of  Medicine 

of  the  plant.  The  latter  absorbs  carbon  dioxide  from  the 
air  and  water  and  inorganic  salts,  including  nitrates,  from 
the  soil.  It  is  generally  assumed,  since  formaldehyde  is 
present  in  minute  amounts  in  functioning  leaves,  and, 
as  pointed  out  earlier  (151),  is  polymerized  to  a  mixture 
of  hexoses,  that  it  is  the  first  product  formed : 

ca  +  H2o  =  HCHO  +  QZ 

6  HCHO  =  C6H1206 

glucose 

The  formation  of  starch  is  not  dependent  on  the  forma- 
tion of  glucose.  Leaves  which  have  been  kept  in  the  dark 
until  they  are  starch-free  and  then  in  the  dark  are  floated 
on  sugar  solutions  quickly  form  starch,  d-glucose  and 
d-fructose  are  most  readily  utilized  for  this  purpose,  but 
certain  plants  can  use  mannose  and  even  galactose  for 
starch  synthesis.  Stereochemical  transformation  is,  of 
course,  necessary  in  these  cases. 

Starch  is  easily  hydrolyzed  by  acids,  but  only  with  great 
difficulty  by  alkalies. 

Dextrines  correspond  to  the  same  empirical  formula  as 
starch,  but  their  molecular  weight  is  much  smaller.  It  is 
assumed  that  there  are  a  large  number  of  dextrines  of 
different  molecular  complexities,  but  only  two  can  be 
readily  distinguished.  Erythrodextrine,  which  gives  a  red 
color  with  iodine,  is  first  formed  by  the  action  of  amylase 
on  starch;  and  achroodextrine,  which  gives  no  color  with 
iodine,  is  formed  somewhat  later. 

Cellulose  is  much  more  resistant  than  is  starch.  It  is 
not  acted  upon  by  enzymes  formed  by  the  higher  animals 


The  Carbohydrates  331 

or  plants,  and  is  not  easily  decomposed  by  acids  or  alkalies. 
On  treatment  with  strong  acids  under  appropriate  condi- 
tions the  only  product  of  its  hydrolysis  is  d-glucose.  Cellu- 
lose is  found  nearly  pure  in  the  cotton  fiber,  in  linen,  and 
in  hemp,  and  is  the  principal  constituent  of  wood.  The 
latter,  however,  contains  about  half  its  dry  weight  of 
incrusting  substances,  known  as  lignin,  pectins,  and  gummy 
substances. 

There  occurs  in  the  covering  of  the  tunicata,  a  group  of 
animals,  a  polysaccharide  tunicin  which  appears  to  be 
identical  with  cellulose.  This  is  the  only  instance  of  the 
occurrence  of  cellulose  in  the  animal  kingdom. 

When  acted  upon  Jby  concentrated  nitric  acid  or  by  a 
mixture  of  nitric  and  sulphuric  acids,  cellulose  is  nitrated. 
According  to  the  conditions,  from  one  to  six  nitro  groups 
are  introduced  in  ester  linkage  for  each  of  the  CeH^Os 
complexes  in  the  molecule.  A  mixture  of  tri-  and  tetra- 
nitrates  dissolved  in  a  mixture  of  alcohol  and  ether  con- 
stitutes collodion. 

Guncotton,.QT  pyroxylin,  is  the  hexanitrate  of  cellulose. 
When  dissolved  in  acetone  or  ethyl  acetate  and  the  solu- 
tion evaporated,  the  residue  in  granular  form  constitutes 
smokeless  powder.  A  mixture  of  cellulose  hexanitrate 
with  nitroglycerine  and  other  substances  forms  ballistite, 
cordite,  blasting  gelatin,  etc. 

Cellulose  forms  several  acetates  when  treated  with 
glacial  acetic  acid  and  acetic  anhydride  in  the  presence  of 
strong  sulphuric  acid.  These  are  insoluble  in  water,  but 
soluble  in  various  organic  solvents.  Artificial  gutta- 
percha  is  produced  by  evaporating  a  solution  of  tetra- 


332     Organic  Chemistry  for  Students  of  Medicine 

acetyl  cellulose  in  acetone.  When  a  solution  of  cellulose 
acetate  in  glacial  acetic  acid  is  poured  into  alcohol,  a 
precipitate  is  formed  which  contains  much  alcohol  and 
burns  without  melting  or  leaving  an  ash  and  is  sold  as 
"  solid  alcohol." 

Cellulose  is  indigestible  in  the  alimentary  tract  of  ani- 
mals, but  certain  bacteria  present  there  ferment  it  with 
the  formation  of  carbon  dioxide,  methane,  hydrogen,  and 
formic,  acetic,  butyric,  valerianic,  and  other  acids.  Cer- 
tain molds  and  saprophytic  plants  secrete  an  enzyme, 
cytase,  which  dissolves  cellulose.  The  products  formed  are 
not  known. 

Cellulose  is  insoluble  in  all  ordinary  solvents,  but 
dissolves  in  an  ammoniacal  solution  of  copper  oxide 
(Schweitzer's  reagent),  and  in  a  solution  of  zinc  chloride 
in  hydrochloric  acid. 

Hemicelluloses  are  important  constituents  of  nut  shells 
and  stony  seeds  of  fruits,  coconut  rind,  etc.,  and  are 
present  in  considerable  amounts  in  the  seeds  of  legumes 
(pea,  bean,  etc.).  On  hydrolysis  with  acids  they  yield 
mannose,  and  those  of  the  legumes  especially  galactose. 
A  certain  amount  of  arabinose  and  xylose  is  also  usually 
formed.  They  are  not  well-characterized  compounds 
therefore,  and  appear  to  be  either  mixtures  of  mannans, 
xylan,  araban,  galactan,  or  complex  carbohydrates  com- 
posed of  complexes  representing  several  kinds  of  sugars. 

Pentosans  are  polysaccharides  which  correspond  to  the 
celluloses,  but  they  yield  on  hydrolysis  a  pentose  sugar. 
Thus  xylan,  which  is  present  in  the  straws  to  the  extent  of 
18-28  %,  yields  xylose ;  and  araban,  which  occurs  in  cherry, 


The  Carbohydrates  333 

peach,  and  other  gums  and  is  the  principal  constituent  of 
gum  arabic,  yields  arabinose  on  hydrolysis.  They  are 
soluble  in  alkalies  and  are  precipitated  by  alkaline  copper 
solutions,  as  copper  xylan,  etc.  Like  the  pentoses,  they 
yield  furfural  on  distillation. 

Pectins  are  the  constituents  of  fruit  juices  which  cause 
the  setting  of  jellies.  Carrots,  beets,  and  rhubarb  are 
especially  rich  in  these  constituents.  Their  chemistry 
is  not  well  understood.  Preparations  of  pectins  made  by 
precipitation  with  alcohol  yield  both  pentoses  and  hexoses, 
and  in  addition  acids  which  seem  to  be  of  the  type  of 
gluconic  acid. 

Plant  Mucilages  are  substances  which  swell  in  water  and 
form  mucilaginous  solutions.  As  examples  may  be  cited 
flaxseed  mucilage,  and  those  of  the  roots  of  salep  and 
althea.  They  yield  both  pentoses  and  hexoses  on  hydrol- 
ysis, but  their  chemistry  has  not  been  thoroughly  studied. 

Gums  contain  the  salts  of  as  yet  unidentified  organic 
acids,  and  yield  these  acids  and  certain  reducing  sugars  on 
hydrolysis.  Arabinose,  xylose,  fucose,  and  galactose 
have  been  identified. 

Glycogen  is  a  polysaccharide  contained  in  animal  and 
in  certain  plant  tissues  which  resembles  soluble  starch  in 
certain  respects,  but  gives  a  reddish  color  with  iodine. 
It  is  soluble  in  cold  water,  forming  an  opalescent  solution. 
It  is  formed  by  the  condensation  of  a  number  of  molecules 
of  glucose,  water  being  separated  in  the  union  of  each  two 
molecules.  It  is  acted  upon  by  amylase,  which  converts 
it  into  maltose  as  in  the  case  of  starch. 

The  glycogen  content  is  higher  in  the  liver  than  any 


334     Organic  Chemistry  for  Students  of  Medicine 

other  tissue,  usually  from  1  to  4  %,  but  the  livers  of  highly 
fed  animals  have  shown  contents  as  high  as  15  %.  It  is 
found  in  other  tissues,  especially  muscles. 

Among  plants  yeast  is  richest  in  glycogen.  When 
animals  or  yeasts  are  starved  the  glycogen  content  de- 
creases markedly,  being  slowly  converted  into  glucose 
which  passes  into  the  blood  to  keep  up  the  normal  content 
of  one  part  to  one  thousand  of  the  latter.  Glycogen  is 
formed  in  the  animal  body  from  certain  sugars  other  than 
glucose,  as  mannose,  levulose,  etc.,  but  only  as  these  are 
converted  into  glucose  (157). 

163.  Chitin  is  a  peculiar  polysaccharide  which  forms  the 
matrix  of  the  shells  of  the  Crustacea  (lobsters,  etc.),  the 
external  covering  and  the  lining  of  parts  of  the  alimentary 
canal  of  insects,  and  the  covering  of  certain  worms  (Hiru- 
dinea).  When  freed  from  incrusting  calcium  salts  in  the 
case  of  lobster  shells  chitin  forms  a  leathery  substance 
which  on  hydrolysis  with  mineral  acids  yields  an  amino 
derivative  of  glucose,  glucosamine,  the  only  nitrogen-con- 
taining carbohydrate. 

On  heating  chitin  with  strong  alkali,  a  treatment  which 
does  not  change  cellulose  or  tunicin,  it  is  decomposed  by 
hydrolysis  into  acetic  acid  and  chitosan,  which  is  soluble 
in  acetic  acid  but  is  precipitated  by  alkalies.  Chitosan  is 
a  base  and  forms  salts  with  acids.  On  boiling  it  with  acids 
it  is  hydrolyzed  to  glucosamine  and  a  further  amount  of 
acetic  acid. 

Glucosamine,  C6HiiO5NH2,  is  an  amino  sugar  derived 
from  many  proteins  on  hydrolysis.  It  contains  an  alde- 
hyde group,  as  is  shown  by  its  formation  of  an  oxime  with 


The  Carbohydrates 


335 


hydroxylamine,  and  a  hydrazone.  Its  constitution  has 
been  approximately  established  by  E.  Fischer,  who  syn- 
thesized it  by  the  following  procedure : 

CH2OH  CH2OH  CH2OH 

I  I  I 

(CHOH)3   +NH3   (CHOH)3      -f-HCN  (CHOH)3 


CHO 

Arabinose 


/NH2 


/ 


NH2 


+  H20 


V^-L-Lv 

N>H 

Arabinose  ammonia 

CH2OH 

CN 

Arabinose  cyanhydrin 

CH2OH 

1 

H—  ( 

:—  OH 
i 

(CHOH) 

1 

HC^ 

CHNK 
COOH 

i,        HO—  C—  H 
CHNH2 

x>0 

cox 

Glucosaminic  acid         Lactone  of  glucosaminic  acid 

CH2OH 


OH 

Glucosamine 


336     Organic  Chemistry  for  Students  of  Medicine 

It  is  not  certain  whether  the  amino  group  is  on  one  or 
the  other  side  of  the  carbon  chain,  and  the  compound  may 
be  either  glucosamine  or  mannosamine.  That  the  amino 
group  is  united  to  the  carbon  atom  neighboring  the  alde- 
hyde is  made  highly  probably  by  the  decomposition  de- 
scribed by  Neuberg,  of  glucosamine  into  erythronic  acid 
(150)  by  boiling  with  barium  hydroxide. 

H       OH   OH 

HOC— CHNH2-  -C C C— CH2OH      Glucosamine 

I     I 

OH    H      H 

OH    OH 

I          I 

HOOC— C C— CH2OH       Erythronic  acid 

I  I 

H       H 

On  treatment  of  glucosamine  with  nitrous  acid  the  amino 
group  is  replaced  by  hydroxyl.  The  resulting  hexose  is 
however  not  glucose  or  mannose.  It  is  known  as  chitose. 
It  does  not  ferment,  and  does  not  yield  a  difficultly  soluble 
osazone.  By  comparison  with  the  synthetically  prepared 
compound,  Fischer  assigned  to  chitose  the  following  cyclic 
structure  :  HQHC CHOH 

I  I 

HOH2C-HC        CH— CHO 


v 


Chitose 

Inulin  (C6HioO5)n  is  a  polysaccharide  entirely  analogous 
to  starch,  which  is  found  as  a  reserve  carbohydrate  in 


The  Carbohydrates  337 

dahlia  roots  and  other  tubers  of  the  Composite.  On 
hydrolysis  it  yields  only  d-fructose.  In  the  plant  tissues 
where  inulin  occurs  there  is  formed  an  enzyme,  inulase, 
which  effects  its  hydrolysis  whenever  growth  begins. 
There  is  no  inulase  in  the  digestive  secretions  of  animals 
and  therefore  no  provision  for  the  utilization  of  this 
carbohydrate. 


CHAPTER   XVI 

THE   CHEMICAL    CHANGES   IN   THE    FERMENTATION 
OF   THE    SUGARS 

164.  The  nature  of  the  chemical  changes  involved  in 
the  fermentation  of  sugars  has  been  very  carefully  investi- 
gated, and  the  mechanism  of  the  change  of  hexose  into 
alcohol  is  fairly  definitely  understood.  On  the  one  hand 
the  method  of  investigation  consisted  of  the  careful  study 
of  the  compounds  which  result  from  the  decomposition  of 
glucose  by  chemical  agents,  especially  alkalies,  since  they 
induce  decompositions  of  a  profound  character  resembling 
a  certain  type  of  fermentation  (lactic  acid).  There  is  a 
certain  degree  of  probability  that  the  cleavage  of  the 
glucose  molecule  by  alkalies  will  follow  the  same  lines  as 
those  on  which  sugar  normally  tends  to  dissociate,  and  it  is 
along  these  lines  that  the  enzymes  of  the  yeast  accelerate 
change. 

On  the  other  hand  the  inquiry  may  be  directed  toward 
testing  under  carefully  regulated  conditions  the  ability  of 
yeast  to  take  any  supposed  intermediary  product  in  the 
process  of  cleavage  in  fermentation  and  to  complete  the 
process  of  conversion  of  this  into  alcohol.  Any  compound 
which  can  be  so  converted  is  regarded  as  a  possible  inter- 
mediary product,  and  any  one  which  cannot  be  converted 
into  alcohol  must  be  excluded. 

Another  procedure  possible  of  application  in  certain 
instances  is  to  conduct  the  trial  with  the  yeast  in  the  pres- 

338 


Fermentation 


339 


ence  of  some  harmless  substance  which  will  combine 
with  a  supposed  intermediary  product  whose  existence  in 
ordinary  practice  is  but  transient,  and  to  remove  it  from 
the  sphere  of  influence  of  the  living  organism,  thus  causing 
its  accumulation.  The  results  of  extensive  inquiry  by 
many  investigators  have  been  the  proposal  of  the  following 
explanations  of  the  process  of  fermentation : 


CHO 


CHO 


COH 
-H_!2CH 


CO 


CHOH 


CHOH 


CHOH 


Glucose 


CHOH 

I 

CH2OH 
ii 


CHOH 

CH2OH 

in 


Unstable  dissociation 
products 


CHO 

i. 


CH3 

Methyl  glyoxal 

CHO 
CHOH 


CHO 
CHO 


CHO 
CO 


CH2OH 

IV 

Gly  eerie  aldehyde 


CH2 

V 


VI 


340     Organic  Chemistry  for  Students  of  Medicine 


CHO 

CO       +H2°     CHOH      -  CH2OH 

I  I  I   . 

CH.3  CH3  CH3 

VII  VIII 

Lactic  acid  Alcohol 

The  central  idea  is  the  alternate  dissociation  and  re- 
addition  of  the  elements  of  water.  When  alkali  acts  on 
glucose,  lactic  acid  is  formed  to  the  extent  of  54  per 
cent  of  the  theoretical  amount,  formic  acid  to  .5-2  per  cent, 
and  40  per  cent  of  a  mixture  of  hydroxy  acids  containing 
four  and  six  carbon  atoms.  About  1  per  cent  of  alcohol 
and  CO2  are  also  formed.  There  is  no  gly  colic  or  oxalic 
acid,  nor  glycol  or  glycerol  formed.  If  lactic  acid  were 
formed  by  a  separation  of  the  carbon  chain  into  two  three- 
carbon  aldehydes  and  subsequent  oxidation  and  reduction, 
the  resulting  lactic  acid  should  be  optically  active,  which 
is  not  the  case  in  lactic  acid  fermentation,  and  this  lends 
support  to  the  view  that  some  three-carbon  aldehyde 
other  thari  gly  cer  aldehyde  is  first  formed. 

Pyruvic  acid,  CH3—  CO—  COOH 
Methyl  glyoxal,  CH3—  CO—  CHO 
Glyceric  aldehyde,  CH3OH—  CHOH—  CHO 
Dihydroxyacetone,  CH2OH—  CO—  CH2OH 

have  all  been  proposed  as  the  most  probable  intermediary 
cleavage  product. 

Methyl  glyoxal  is  not  fermentable  by  yeasts,  while  the 
results  are  positive  for  glyceraldehyde  and  dihydroxy 


Fermentation  341 

acetone.  The  most  satisfactory  explanation  is  probably 
the  following : 

C6H1206  =  2  CH3— CO— COOH  +  4  H 

Pyruvic  acid 

2  CH3— CO— COOH  =  2  CH3— CHO  +  2  CO2 
2  CH3— CHO  +  4  H  =  2  CH3— CH2OH 

This  scheme  receives  strong  support  from  the  now  well- 
substantiated  observation  that  yeast  juice  free  from  living 
cells  contains  the  enzyme,  carboxylase,  which  accelerates 
the  decomposition  of  pyruvic  acid  into  acetaldehyde  and 
carbon  dioxide.  Acetaldehyde  is  readily  reduced  to  alcohol. 

Another  theory  of  alcoholic  fermentation  deserves  to  be 
mentioned.  Schade  showed  that  lactic  acid  treated  with 
dilute  sulphuric  acid  formed  acetaldehyde  and  formic  acid  : 

CH3— CHO  H— COOH  =  CH3— CHO +H— COOH 

showing  a  tendency  for  this  line  of  cleavage  which  might  be 
accelerated  by  a  yeast  enzyme.  Formic  acid  is  rapidly 
decomposed  catalytically  by  means  of  metallic  rhodium 
into  hydrogen  and  carbon  dioxide.  Schade  held  that 
the  latter  reaction  might  also  be  catalyzed  by  a  ferment, 
thus  producing  through  lactic  acid  as  a  first  product  from 
hexose,  acetaldehyde,  and  hydrogen  in  a  nascent  state  to 
reduce  it,  together  with  one  molecule  of  carbon  dioxide 
for  each  molecule  of  alcohol  produced.  This  is  the  pro- 
portion actually  observed  in  yeast  fermentation.  Yeasts 
do  not  however  ferment  a  mixture  of  acetaldehyde  and 
sodium  formate. 


342     Organic  Chemistry  for  Students  of  Medicine 

Lactic  Acid  Fermentation  is  equally  in  harmony  with  the 
assumption  that  pyruvic  acid  is  first  formed  from  hexose. 
Lactic  acid  can  be  oxidized  to  pyruvic  acid  or  the  latter 
reduced  to  lactic  acid  : 


+21 


CHOH       _         CO  CHOH 


:OOH  COOH         COOH 

Lactic  acid  Pyruvic  acid  Lactic  acid 

Butyric  Acid  Fermentation.  —  Bacillus  holobutyricus 
has  been  shown  capable  of  converting  lactic  acid  into 
butyric  acid  in  considerable  amounts.  The  products 
are  n-butyric  acid,  carbon  dioxide,  and  hydrogen.  The 
destruction  of  lactic  acid  by  bacteria  leads  to  the  accumu- 
lation of  appreciable  amounts  of  the  following  products : 
CHg  CH3  CH3  H  CO2  H2 

Carbon  Hy- 

CHOH       CH2       .COOH       COOH      ***"     d">i" 

Acetic  Formic 

COOH        COOH 

Lactic  Propionic 

acid  acid 

The  most  plausible  explanation  of  butyric  acid  fer- 
mentation from  lactic  acid  is  that  based  on  the  condensa- 
tion of  acetaldehyde  with  acetic  acid,  analogous  to  the 
condensation  of  benzaldehyde  with  acetic  acid  to  form 
cinnamic  acid  in  Perkin's  synthesis  (207) : 

CH3— CH|0  +  H2|HC— COQH 

=  CH3— CH=CH— COOH 

The  resulting  crotonic  acid  would  be  reduced  to  butyric 
acid. 


Fermentation  343 

FORMATION   OF   FATTY   ACIDS   FROM 
CARBOHYDRATES 

165.  The  nature  of  the  process  by  which  carbohydrate 
is  changed  into  fatty  acids  for  fat  synthesis  within  the 
body  is  not  fully  understood.  There  is  satisfactory  ex- 
perimental proof  that  pigs  and  geese  have  become  fat  at 
the  expense  of  the  carbohydrate  moiety  of  the  diet.  A 
significant  fact  which  any  hypothesis  must  recognize  is  the 
existence  among  the  ordinary  fatty  acids  of  those  only 
which  contain  an  even  number  of  carbon  atoms,  chiefly 
12,  14,  16,  and  18  carbon  atom  acids.  Myristic  and 
palmitic  acids  with  14  and  16  carbon  chains  refute  the 
supposition  that  three  molecules  of  hexose  condense  to 
form  a  chain  which  by  reduction  of  hydroxyls  and  oxida- 
tion of  the  terminal  carbonyl  could  form  a  fatty  acid. 

An  adequate  explanation  must  account  for  the  addition 
of  two  carbon  atoms  at  a  time  to  some  of  the  lower  members 
of  the  series,  or  to  a  compound  which  is  readily  oxidizable 
to  a  fatty  acid. 

Lieben  has  shown  that  butyric  aldehyde  can  condense 
with  acetaldehyde  in  the  presence  of  dilute  alkali,  but  the 
resulting  aldehyde  is  not  a  straight  chain : 

CHs— CH2— CH2— CHO  +  CH3— CHO 

Butyric  aldehyde  Acetaldehyde 

=  CH3-CH2-CH-CHO 

I 
CHOH 

CH3 


344     Organic  Chemistry  for  Students  of  Medicine 

This  cannot  therefore  be  considered  a  very  probable 
explanation  of  what  takes  place  in  the  animal  body. 

The  most  plausible  hypothesis  yet  advanced  concerning 
the  biological  method  of  forming  fats  is  that  of  Smedley, 
who  condensed  croton  aldehyde  with  pyruvic  acid,  and 
by  oxidizing  the  resulting  ketonic  acid  with  hydrogen 
peroxide,  CO2  was  split  off  and  the  doubly  unsaturated 
sorbic  acid  was  formed  : 

1.  CH3— CH  =  CH— CHO  +  CH3— CO— COOH 

Croton  aldehyde  Pyruvic  acid 

=  CH3— CH  =  CH— CH  =  CH— CO— COOH 

2.  CHa— CH  =  CH— CH  =  CH— CO— COOH  +  O 

=  CHs— CH  =  CH— CH  =  CH— COOH  +  CO, 

Sorbic  acid 

It  is  easy  to  understand  how  the  double  bonds  could  be 
removed  from  such  an  acid  by  reduction. 

Smedley  suggests  pyruvic  acid  and  acetaldehyde  as  the 
starting  point  for  fat  synthesis  in  the  body.  The  following 
reactions  will  illustrate  the  process : 

3.  CH3— CO— COOH  +  CHs— CHO 

Pyruvic  acid  Acetaldehyde 


=  CH3— CH  [OH]  -€H  m  —CO— COOH 


4.  CH3— CH  =  CH— CO— COOH  +  O 

Pentylenic  a-keto  acid 

=  CH3— CH  =  CH— COOH  +  CO2 

Crotonic  acid 

5.  CHs— CH  =  CH— COOH  +  2H 

=  CH3— CH2— CH2— COOH 

Butyric  acid 


Fermentation  345 


6.  CH3— CH  =  CH— CO— jCOOjH        —CO, 

Pentylenic  a-keto  acid 

=  CH3— CH  =  CH— CHO 

Crotonic  aldehyde 

7.  By  reactions  1  and  2  sorbic  acid  is  formed. 

8.  CH3— CH  =  CH— CH  =  CH— COOH  +  4  H 

Sorbic  acid 

=  CH3— CH2— CH2— CH2— CH2— COOH 

Caproic  acid 

By  an  extension  of  this  synthesis  the  higher  fatty  acids 
would  result. 


CHAPTER   XVII 
THE   AROMATIC    COMPOUNDS 

166.  The  hydrocarbons  of  the  aliphatic  series,  or  the 
fatty  compounds,  are  not  products  of  animal  or  plant 
metabolism,  with  the  exception  of  methane,  which 
results  from  the  bacterial  fermentation  of  cellulose.  None 
of  them  have  highly  agreeable  odors.  There  are  in  cer- 
tain products  of  vegetable  origin  compounds  which  con- 
tain only  carbon  and  hydrogen,  and  are  very  poor  in 
hydrogen,  suggesting  compounds  of  a  highly  unsaturated 
character,  as  isoprene  (82).  These  differ  in  every  re- 
spect in  their  properties  from  the  unsaturated  or  the  sat- 
urated hydrocarbons  of  the  aliphatic  series.  Thus  toluene, 
CjHs,  from  Tolu  balsam,  and  cymene,  Ci0Hi4,  from  oil  of 
eucalyptus,  oil  of  thyme,  oil  of  caraway,  and  other  essen- 
tial oils,  are  hydrocarbons  of  pronounced  and  charac- 
teristic aromatic  odors.  They  do  not  form  addition 
products  with  the  halogens  as  do  the  unsaturated  hydro- 
carbons. Benzoic  acid,  which  is  found  in  gum  benzoin, 
in  cranberries,  and  elsewhere  in  plants,  yields  when  its 
calcium  salt  is  subjected  to  dry  distillation,  a  hydro- 
carbon, CeHe,  benzene. 

Toluene  is  oxidized  to  benzoic  acid  and  is  therefore 
closely  related  to  benzene.  Cymene  yields  on  oxidation  a 
dibasic  acid,  teraphthalic  acid,  which  on  distillation  of  its 
calcium  salt  likewise  yields  benzene. 

346 


The  Aromatic  Compounds  347 

Benzene  may  be  regarded  as  the  mother  substance  of  a 
large  number  of  compounds  of  great  biological  and  tech- 
nical interest,  and  its  chemistry  should  be  considered  in 
some  detail.  The  constitution  of  its  molecule  was  first 
suggested  by  Kekule  in  1867,  and  was  based  principally 
on  the  following  evidence  :  Since  benzene  does  not 
behave  like  an  unsaturated  compound,  its  structure  must 
be  of  a  special  nature  to  account  for  this  property,  for  it 
is  not  possible  to  write  the  formula  CeH6  as  an  open  chain 
without  the  employment  of  double  or  triple  bonds.  It  has 
therefore  a  closed  ring  structure. 

Benzene  is  formed  when  acetylene  is  passed  through  a 
heated  tube  or  subjected  to  high  pressure.  The  molec- 
ular weight  is  78,  so  it  follows  that  in  the  polymerization 
three  molecules  of  acetylene  condense  into  one  : 

CH 


X-ITT 

Ill 

CH      CH 


/TTT  v-/ 

CH  CH 

Benzene  (Kekulfi  formula) 

The  correctness  of  the  view  that  the  benzene  molecule 
represents  a  closed  ring  of  six  carbon  items  linked  alter- 
nately by  single  and  double  bonds  is  supported  by  the 
observation  that  when  the  vapors  of  benzene  mixed  with 
hydrogen  are  passed  through  a  heated  tube  containing 
finely  divided  nickel,  six  atoms  of  hydrogen  are  absorbed 
and  hexamethylene  (112)  is  formed  : 


348    Organic  Chemistry  for  Students  of  Medicine 

CH  CH2 

/\  /\ 

HC      CH  H2C      CH2 

I        II     +6H  |       | 

HC      CH  H2C     CH2 

V  \/ 

CH  CH, 

Benzene  ^  Hexamethylene 

Kekule  also  emphasized  the  fact  that  all  of  the  six 
hydrogen  atoms  of  benzene  are  equal,  since  each  is  attached 
to  a  carbon  which  is  alternately  singly  and  doubly 
bound,  i.e.  to  carbon  atoms  which  are  alike.  If  this  is 
true  there  should  be  but  one  mono-substitution  product 
of  benzene  as  chlor,  brom,  nitro,  amino,  etc.,  benzene, 
all  of  which  derivatives  are  known.  Actually  but  a 
single  compound  of  these  types  is  known.  On  the  nor- 
mal aliphatic  hydrocarbon  containing  six  carbon  atoms, 
three  isomeric  mono-substitution  products  exist,  depend- 
ing on  whether  the  substituting  group  is  at  1,  2,  or  3, 

On  the  other  hand,  theory  calls  for  three  disubstitu- 
tion  products  of  such  a  hexagonal  ring,  and  three  dichlor, 
dinitro,  dihydroxy,  etc.,  benzenes,  but  no  more  than 
three,  are  known.  These  are  called  ortho-,  meta-,  and 
para-  derivatives  (designated  as  o-,  m-,  and  p-)  according 


Ortho  Meta 


The  Aromatic  Compounds  349 

to  whether  the  substituting  groups  occupy  positions  on 
neighboring  carbon  atoms  (1:2)  or  on  atoms  separated 
by  one  (1 :  3)  or  by  two  carbon  atoms  (1 : 4)  respectively. 
The  position  1 :  5  is  the  same  as  1 :  3  and  1 :  6  is  the  same 
as  1:2.  The  number  of  isomers  should  be  the  same  for 
disubstitution  products  whether  these  are  similar  or  dis- 
similar. 

There  should  be,  according  to  theory,  three  isomers  of 
a  trisubstitution  product  of  benzene  provided  all  substi- 
tuting groups  are  similar,  but  more  if  two  are  similar  and 
one  dissimilar. 


x 

Adjacent  or  vicinal          Symmetrical  Unsymmetrical 

(1:2:3)  (1:3:5)  (1:3:4) 

Of  the  vast  number  of  derivatives  of  benzene  which 
have  been  prepared  and  studied,  theory  has  in  all  cases 
accorded  with  observation. 

It  is  essential,  if  we  accept  this  structure  for  benzene, 
to  assume  that  the  double  bonds  are  alternating  between 
the  1 : 6  and  the  1 : 2  positions,  otherwise  there  should 
be  observed  different  properties  for  a  disubstitution  prod- 
uct in  which  the  groups  were  separated  by  a  single  and 
double  bond  respectively.  Such  a  vibration  was  assumed 
by  Kekule.  To  obviate  this  difficulty,  since  but  one 
ortho  disubstitution  product  has  been  observed,  the 
centric  formula  was  proposed  by  Armstrong.  According 


350     Organic  Chemistry  for  Students  of  Medicine 

to  his  assumption  the  fourth  bond  of  each  carbon  atom  in 
the  ring  is  directed  toward  the  center: 


HC<     >CH 


Such  a  structure  accounts  for  the  extreme  stability  of 
benzene,  which  is  much  greater  than  that  of  the  aliphatic 
hydrocarbons,  and  also  accounts  for  the  peculiar  isom- 
erism  of  its  derivatives  and  for  its  "  aromatic  "  char- 
acter. The  six-membered  ring  is  referred  to  as  the 
benzene  nucleus,  and  since  many  derivatives  of  benzene 
are  known  in  which  one  or  more  aliphatic  groups  replace 
the  hydrogen  atoms  of  the  nucleus,  these  are  called  "  side 
chains."  Substitution  can  be  effected  either  in  the 
nucleus  or  in  the  side  chain. 

DETERMINATION   OF   POSITION   OF   SUBSTITUTING 
GROUPS   IN   THE   NUCLEUS 

167.  This  has  been  determined  by  very  extensive  and 
elaborate  study  for  a  few  substitution  products  of  benzene 
by  a  method,  the  principle  of  which  was  enunciated  by 
Korner.  It  depends  upon  the  fact  that  when  a  third 
substituent  y  is  introduced  into  an  ortho  compound,  in 
which  both  substituting  groups  are  similar,  but  two 
isomers  can  be  formed.  This  is  true  whether  y  is  like  or 
unlike  x : 


The  Aromatic  Compounds  351 


(1)  (2)  (3)  (4) 

Two  and  3  are  the  same  and  1  and  4  are  the  same. 
In  the  case  of  the  meta  compound  three  isomers  can  be 
formed : 


y 

While  in  the  case  of  a  para  compound  but  one  trisubsti- 
tution  product  can  result: 

x 


No  matter  what  position  y  may  take,  it  occupies  the  same 
relative  positions  with  respect  to  the  other  substituents, 
viz.  it  is  always  in  the  ortho-  position  to  one  and  in  the 
meta  position  to  the  other.  The  experimental  evidence 
in  support  of  the  theory  of  structure  consists  in  the  prep- 
aration of  compounds  having  the  percentage  composi- 
tion called  for  by  the  theory  and  efforts  to  separate  the 
product  by  crystallization,  distillation,  etc.,  into  fractions 


352    Organic  Chemistry  for  Students  of  Medicine 

which  have  the  same  composition,  but  different  physical 
properties;  i.e.,  isomers.  The  fact  that  patient  search 
has  revealed  the  existence  of  all  the  isomers  demanded 
by  theory,  and  in  no  instance  more  than  these,  is  convinc- 
ing evidence  of  the  validity  of  the  theory. 

Benzene,  CeH6,  is  a  colorless  liquid  with  a  character- 
istic odor,  which  boils  at  80°.  When  strongly  cooled  it 
crystallizes,  the  crystals  melting  when  warmed  to  5.4°. 
Its  specific  gravity  at  20°  is  .874.  It  burns  with  a 
smoky  flame  and  its  vapors  are  inflammable.  It  dis- 
solves in  all  proportions  in  alcohol  or  ether,  but  is  in- 
soluble in  water.  It  dissolves  fats,  resins,  etc.,  and  is 
a  good  solvent  for  sulphur,  phosphorus,  iodine,  and 
many  other  substances. 

The  benzene  of  commerce,  also  called  benzole,  was  for- 
merly obtained  from  coal  tar,  which  on  distillation  yields 
in  the  fraction  obtained  up  to  150°,  from  3-5  per  cent  of 
a  mixture  of  benzene  and  its  homologues,  toluene  and 
xylene.  Recently  Rittmann  has  perfected  a  process  by 
means  of  which  the  aliphatic  hydrocarbons  of  petro- 
leum can  be  made  to  yield  10-15  per  cent  of  these  cyclic 
hydrocarbons.  This  process  consists  in  heating  the  petro- 
leum under  pressure  for  a  time,  and  then  distilling  the 
product.  The  principle  involved  depends  upon  the 
dissociation  of  the  aliphatic  hydrocarbons  under  these 
conditions  into  various  unsaturated  hydrocarbons,  among 
which  are  a  small  content  of  acetylene  and  of  its  alkyl 
derivatives  (see  p.  164).  At  high  temperatures  and  pres- 
sures acetylene  condenses  to  benzene,  an  irreversible 
reaction. 


The  Aromatic  Compounds  353 

PHYSIOLOGICAL   PROPERTIES   OF   BENZENE 

168.  The  aliphatic  and  aromatic  hydrocarbons  show 
considerable  differences  in  their  physiological  properties. 
The  lower  members  of  the  methane  series  produce  sleep 
if   inhaled,   and   death  by   asphyxia.     The   toxicity   in- 
creases as  the  carbon  atoms  become  more   numerous. 
Hexane  is  actively  intoxicant,  producing  a  long  stage  of 
excitement  followed  by  deep  anesthesia.     It  acts  on  the 
sensory  side.     Benzene  and  other  aromatic  hydrocarbons 
act  principally  on  the  motor  centers,  producing  convul- 
sions and  paralysis.     Benzene  has  furthermore  a  selective 
toxic   effect   for   the  white   blood   corpuscles,  producing 
leucopenia,   and   is   employed   in   medicine   in   cases   of 
leucemia. 

HOMOLOGUES   OF   BENZENE 

169.  Friedel  and  Crafts  Reaction.     When  benzene  is 
treated  with  an  aliphatic  halogen  compound  in  the  pres- 
ence of  aluminum  chloride  a  reaction  takes  place  in  which 
hydrochloric  acid  gas  is  evolved  and  the  aliphatic  group 
is  linked  to  the  benzene  nucleus : 


+CH3C1   +A1Cl3 


For  the  sake  of  simplicity  the  hexagonal  ring  is  employed 
to  represent  benzene. 

By  the  employment  of  the  homologues  of  methyl  chlo- 
ride, ethyl,  propyl,  etc.,  groups  can  be  substituted  for  a 
hydrogen  atom  in  the  benzene  ring.  The  benzene  nucleus 

2A 


354     Organic  Chemistry  for  Students  of  Medicine 

less  one  hydrogen  is  called  the  phenyl  group.  Several  'of 
these  compounds  are  of  great  importance,  and  their 
chemical  behavior  is  of  considerable  interest. 

Toluene,  CeHsCHs,  is  formed  by  the  dry  distillation  of 
tolu  balsam  and  of  many  resins.  It  occurs  in  coal  tar 
and  is  separated  from  it  by  distillation  along  with  benzene. 
It  boils  at  110°  and  by  fractional  distillation  can  be  sep- 
arated from  benzene  and  other  homologues.  It  is  much 
employed  as  an  antiseptic  in  biochemical  work. 

When  oxidized  by  chromyl  chloride,  CrQjC^,  it  is 
converted  by  the  oxidation  of  the  "  side  chain,"  the 
methyl  group,  into  an  aldehyde,  C6H5CHO,  called  benzal- 
dehyde,  which  may  be  regarded  as  phenyl  formaldehyde. 
More  vigorous  oxidizing  agents  convert  toluene  directly 
into  benzoic  acid,  CeHsCOOH,  which  is  the  acid  corre- 
sponding to  benzaldehyde.  It  may  be  regarded  as  phenyl 
formic  acid.  It  has  been  noted  that  on  heating  the  cal- 
cium salt  of  benzoic  acid  carbon  dioxide  is  removed  from 
the  carboxyl  group  and  benzene  is  formed.  The  follow- 
ing transformations  for  toluene  illustrate  -the  general 
behavior  of  the  compounds  containing  both  an  aromatic 
and  an  aliphatic  group  : 

CHO  COOH 

+  20  fO          I  -C02 


Toluene  Benzaldehyde         Benzoic  Acid  Benzene 

Longer  side  chains  as  in  ethyl-,  propyl-,  isopropyl-,  etc., 
benzene  oxidize,  no  matter  how  many  carbon  atoms  con- 


The  Aromatic  Compounds  355 

tained  in  them,  into  carboxyl.  Hence  the  three  deriva- 
tives just  named  all  yield  benzoic  acid. 

170.  Chlor  toluenes.  It  is  obvious  that  derivatives 
of  two  types  can  be  produced  by  the  action  of  chlorine 
on  toluene,  viz.  derivatives  in  which  the  chlorine  occu- 
pies the  ortho-,  meta-  or  para-  position  to  the  methyl 
group  in  the  benzene  nucleus,  or  those  in  which  one,  two 
or  three  of  the  hydrogen  atoms  in  the  methyl  group  are 
replaced  by  chlorine.  The  position  taken  by  chlorine 
when  it  reacts  with  toluene  depends  upon  the  conditions 
under  which  the  reaction  takes  place.  At  low  temper- 
atures and  in  the  absence  of  light  ortho-  and  para-chlor 
toluenes  are  formed  in  about  equal  proportions,  with 
very  little  of  the  meta-  compound.  When  Cl  acts  on  p- 
toluidine  (176)  the  Cl  enters  the  m-  position  to  the  CH3 
group.  The  action  is  greatly  accelerated  by  the  presence 
of  halogen  carriers,  such  as  iodine,  ferric  chloride,  antimony 
trichloride,  etc. 

At  high  temperatures  (110°)  even  in  the  absence  of 
light  chlorine  substitutes  in  the  side  chain  exclusively. 
In  the  presence  of  halogen  carriers,  however,  the  chlorine 
enters  the  nucleus  even  at  high  temperatures. 

At  ordinary  temperatures  in  direct  sunlight  the  chlorine 
enters  the  side  chain  exclusively. 

The  terms  chlor-,  brom-,  and  iodo-toluenes  refer 
to  the  o-,  m-,  p-,  derivatives.  The  derivatives  in 
which  the  halogen  is  in  the  side  chain  are  named  as 
follows  : 


Benzyl  chloride  Benzal  chloride  Benzo  trichloride 


356     Organic  Chemistry  for  Students  of  Medicine 

The  group  CeH5  —  CH2  —  is  called  the  benzyl-radical; 
C6H5CH=  benzal-,  and  C6H5CH=  benzo-,  radical.  The 
behavior  of  these  will  be  further  described  later. 

171.  Xylenes.  Dimethyl,  benzenes,  C6H4(CH3)2,  are 
formed  by  the  Fittig  reaction,  employing  brom  toluenes 
and  methyl  bromide  : 

CH3  CH3 


CH3Br  ,        , 


CH3 

The  same  result  is  obtained  by  means  of  the  Friedel 
and  Crafts  reaction  (169),  by  means  of  which  all  of  the 
hydrogens  of  the  benzene  nucleus  have  been  successively 
replaced  by  methyl  groups. 

Ortho-,  meta-,  and  para-xylenes  can  yield  by  oxidation 
either  monobasic  o-,  m-,  and  p-toluic  acids,  or  the  three 
corresponding  dibasic  acids : 

COOH       COOH 

COOH 

COOH   l\/>  COOH 

COOH 

Phthalic  acid  Isophthalic  acid  Teraphthalic  acid 

Phthalic  acid  when  heated  loses  a  molecule  of  water, 
forming  an  anhydride.  This  is  employed  extensively  in 
the  preparation  of  dyes. 

172.  Mesitylene,  symmetrical  trimethyl  benzene, 
C6H3(CH3)3,  is  formed  by  methods  analogous  to  the  for- 


The  Aromatic  Compounds 


357 


mation  of  xylene  (171),  and  also  by  the  polymerization  of 
acetone  in  the  presence  of  strong  sulphuric  acid : 


CH3 


C-H 


C— CH3 


CH3 
C 

H— C        C— H 

I         II      - 

CH3— C        C— CH3  +  3H2O 
/ 

C 
H 


Another  class  of  hydrocarbons  is  known  in  which  two 
or  three  phenyl  groups  replace  as  many  hydrogen  atoms 
in  the  methane  group  : 


CeHs — CH3 

Toluene 

or 
phenyl  methane 


CH2 

C6H6/ 

Diphenyl  methane 


C6H5— CH 

Triphenyl  methane 


Diphenyl  methane  is  formed  by  the  interaction  of 
benzyl  chloride  with  benzene  by  the  Friedel  and  Crafts 
reaction. 

Triphenyl  methane  is  prepared  in  large  quantities  in 
the  dye  industry  from  chloroform,  CHC13,  and  benzene, 
likewise  by  the  Friedel  and  Crafts  reaction  (169). 

173.   Cymene,  or  methyl-p-isopropyl  benzene,  occurs 


358    Organic  Chemistry  for  Students  of  Medicine 

CH3 


CH3   CH3 

in  numerous  essential  oils.     It  yields  successively  on  oxi- 
dation p-toluic  acid  and  teraphthalic  acids  (171). 

Halogen  Derivatives  of  Benzene.  Chlorine  acts  upon 
benzene,  substituting  its  hydrogen  atoms  in  a  manner 
analogous  to  the  aliphatic  hydrocarbons. 

Cl 
f\ 
+  2C1=  +  HC1 


Benzene  Chlor  benzene 

The  action  is  greatly  accelerated  by  the  presence  of 
iodine.  This  action  is  in  part  due  to  the  fact  that  in  the 
formation  of  iodine  chlorides,  IC1  and  IC13,  the  molecule 
of  chlorine  C^  is  broken  up  with  the  formation  of  nascent 
chlorine;  and  in  part  to  the  instability  of  the  chlorides 
of  iodine  which-  causes  them  to  dissociate  into  active, 
nascent,  chlorine.  There  will  be  in  the  system  containing 
chlorine  and  iodine,  some  of  the  chlorides  of  iodine  to- 
gether with  their  dissociation  products. 

Bromine  likewise  acts  directly  on  benzene  with  the 
evolution  of  hydrobromic  acid  gas.  The  action  is  greatly 
accelerated  by  the  presence  of  metallic  aluminum. 


The  Aromatic  Compounds  359 

Benzene  is  not  acted  upon  directly  by  iodine,  but 
iodo  benzene  can  be  prepared  from  aniline  by  the  diazo 
reaction  (177). 

The  halogen  derivatives  of  benzene  are  more  stable 
than  the  aliphatic  halogen  compounds.  The  halogen  is 
not  replaceable  by  other  groups,  as  hydroxyl,  etc. 

174.  Nitrobenzene  is  produced  when  concentrated 
nitric  acid  acts  upon  benzene.  This  action  is  in  marked 
contrast  to  the  behavior  of  the  aliphatic  compounds,  which 
cannot  be  directly  nitrated. 


+HN03  =|  +  H20 

I— NO2 

Nitrobenzene 

Nitrobenzene  is  a  yellowish  oily  liquid,  which  crystal- 
lizes when  cooled  and  melts  at  3°.  It  boils  without  decom- 
position at  210°.  It  has  the  odor  of  bitter  almonds  and 
is  employed  as  a  scent  for  soap.  It  is  but  slightly  soluble 
in  water,  but  dissolves  in  alcohol  and  ether  and  in  con- 
centrated sulphuric  acid.  From  the  latter  solution  it  is 
precipitated  unchanged  on  dilution  with  water.  Nitro- 
benzene is  prepared  on  a  large  scale  for  the  manufacture 
of  aniline. 

175.  Aniline,  C6H5NH2,  aminobenzene,  results  from  the 
action  of  nascent  hydrogen  on  nitrobenzene : 


+  6H  = 


Aniline 


360     Organic  Chemistry  for  Students  of  Medicine 

Aniline  may  be  regarded  as  a  substituted  ammonia. 
The  benzene  nucleus  with  one  hydrogen  atom  re- 
moved is  termed  the  phenyl  group  and  is  commonly  ab- 
breviated to  C6H5 —  except  where  the  illustration  of 
structure  is  desired.  Aniline  may  therefore  be  called 
phenyl  amine.  It  is  a  weak  base,  but  forms  salts  with 
acids.  From  these  the  free  base  is  liberated  by  treat- 
ment with  alkalies.  It  is  appreciably  soluble  in  water, 
and  readily  so  in  alcohol  and  ether.  It  has  a  character- 
istic odor  and  is  highly  toxic,  producing  muscular  spasms 
of  central  origin  and  causing  destruction  of  the  red  blood 
corpuscles. 

The  presence  of  an  amino  group  on  the  benzene  nucleus 
greatly  increases  the  ease  with  which  the  other  hydrogen 
atoms  can  be  substituted.  Thus  bromine  acts  but  slowly 
on  benzene  and  by  direct  action  the  principal  end-product 
is  monobrom  benzene,  while  it  reacts  readily  with  aniline, 
forming  symmetrical  tribrom  aniline  : 


+  6Br=  +3HBr 

NH2 


The  favorable  influence  of  the  amino  group  on  either 
halogenation  or  nitration  is  so  great  that  in  order  to  pre- 
pare the  monobrom  or  mononitro  aniline  the  amino 
group  must  be  acetylated.  This  is  effected  by  boiling 
aniline  with  glacial  acetic  acid.  The  acetyl  group  serves 
to  "  protect  "  the  benzene  nucleus : 


The  Aromatic  Compounds  361 


+HOOC—  CH3=  +H20 

NH2  \/  \NH-CO—  CH-, 

Aniline  Acetic  acid  Acetanilide 

Acetanilide  is  a  colorless  crystalline  substance,  which 
melts  at  116°  and  boils  at  304°.  It  is  an  important 
antipyretic.  It  is  hydrolyzed  into  aniline  and  acetic 
acid. 

176.  Alkyl  Anilines.  Aniline  will  react  with  one  or 
two  molecules  of  alkyl  halide  to  form  alkyl  anilines  : 

C6H5—  NH2  +  CH3I  =  C6H5—  NH—  CH3  +  HI 

/CH3 

C6H5—  NH-CH3  +  CH3I  =  C6H5—  N<         +  HI 

XCH3 

The  dimethyl  anilines  are  readily  prepared  by  boiling 
aniline  with  methyl  alcohol  and  hydrochloric  acid. 
Methyl  chloride  is  formed  progressively  as  the  reaction 
proceeds  and  uses  it  up.  Other  alkyl  groups  can  be  in- 
troduced into  aniline  by  employing  the  corresponding 
alcohols. 

The  alkyl  anilines  are  stronger  bases  than  aniline. 

The  methyl  derivatives  of  aniline  in  which  the  alkyl 
groups  occupy  a  position  on  the  benzene  nucleus  are 
known  respectively  as  o-,  m-,  and  p-toluidines. 


Diphenyl  Amine,          /NH,  is  a  crystalline  compound 

C6H5/ 
which  melts  at  54°  and  boils  at  310°.     It  is  prepared  by 


362     Organic  Chemistry  for  Students  of  Medicine 

heating  aniline  hydrochloride  with  aniline  under  pressure 
at  240°  : 

C6H5—  NH2  -  HC1  +  C6H5NH2  =  (C6H5)2  =  NH  +  NH4C1 

Owing  to  the  influence  of  the  negative  character  of  the 
phenyl  groups  the  remaining  hydrogen  attached  to  the 
nitrogen  in  diphenyl  amine  behaves  like  acid  hydrogen 
and  is  replaceable  by  metals.  By  heating  the  potassium 
compound  of  diphenyl  amine  with  brom  benzene,  there  is 
formed  triphenyl  amine  : 


v 
^NK+C6H5Br  =  (C6H5)3=N  +  KBr 

'  Trihenl  amine 


Triphenyl  amine 

177.  Diazobenzene,  C6H5—  N  =  N—  OH.  There  is  a 
very  marked  difference  in  the  behavior  of  aniline,  a  pri- 
mary amine  of  the  aromatic  series,  and  of  the  aliphatic 
primary  amines.  The  former  are  converted  into  the 
corresponding  alcohols  (43),  while  the  latter  form  diazo 
compounds  : 


NH2  +  HNO2  XN  =  N— OH+H2O 

•       Aniline  Diazobenzene 

Diazobenzene  results  from  aniline.  It  behaves  like  a 
strong  base  aad  is  unknown  in  the  free  state,  since  it  is  so 
unstable  that  it  decomposes  with  an  explosion.  Its  salts 
are  crystalline  and  are  safe  only  in  a  moist  state,  since 
they  decompose  violently  when  struck  or  heated.  The 


The  Aromatic  Compounds  363 

salts  of  diazobenzene  with  mineral  acids  are  called  dia- 
zonium  salts.  They  are  readily  soluble  in  water,  less 
soluble  in  alcohol,  and  are  not  soluble  in  ether. 

An  aqueous  solution  of  a  diazonium  salt  is  decomposed 
on  heating,  with  the  formation  of  phenol : 

C6H5— N  =  N— Cl  +  H2O  =  C6H5OH  +  N2  +  HC1 

Phenol 

This  offers  a  ready  means  of  replacing  the  amino  group 
by  hydroxyl  on  the  benzene  nucleus.  Since  nitro  com- 
pounds are  converted  into  amines  by  reduction,  nitro 
groups  are  also  replaceable  indirectly  by  hydroxyl. 

On  boiling  a  diazonium  salt  with  absolute  alcohol,  it  is 
decomposed  with  the  evolution  of  nitrogen  and  the  for- 
mation of  benzene : 

C6H5— N  =N-C1  +  2  H  =  C6H6  +  N2  +  HC1 

The  hydrogen  is  derived  from  the  alcohol,  a  portion  of 
which  is  converted  into  aldehyde : 

CH3— CH2OH  =  CH3— CHO  +  2  H 

In  this  case  the  diazonium  group  is  replaced  by  hydrogen. 

The  diazonium  group  can  also  be  replaced  by  halogen. 
Thus  if  a  warm  solution  of  potassium  iodide  is  added  to  a 
solution  of  diazonium  sulphate,  iodobenzene  is  formed : 

C6H5-N=N-HS04  +  KI  =  C6H5I  +  N2  +  KHSO4 

Similarly  by  adding  cuprous  chloride  in  concentrated 
hydrochloric  acid,  cuprous  bromide  in  hydrobromic  acid, 
or  cuprous  cyanide  in  potassium  cyanide,  to  a  solution 
of  a  benzene  diazonium  salt,  chlor,  brom,  or  cyano  benzene 
respectively  are  formed.  This  is  known  as  the  Sand- 


364     Organic  Chemistry  for  Students  of  Medicine 

meyer  reaction.  It  offers  a  ready  means  of  synthesis  for 
compounds  which  cannot  be  formed  directly.  Thus 
chlorine  does  not  enter  the  meta  position  to  the  methyl 
group  in  toluene,  but  does  in  the  chlorination  of  p-tolui- 
dine.  The  amino  group  can  thereafter  be  removed  by  the 
diazo  reaction,  yielding  meta-chlor-toluene. 

178.  Benzene  Sulphonic  Acid,  CeH5  —  SOsH,  is  formed 
by  the  action  of  concentrated  sulphuric  acid  on  benzene. 
It  is  a  hygroscopic  substance  which  melts  at  50°.  Its 
aqueous  solutions  are  strongly  acid  and  it  forms  salts 
which  crystallize  well. 

On  heating  with  acids  it  is  hydrolyzed  into  sulphuric 
acid  and  benzene. 


./o 

g  -  /~\       -l-TT  O       Benzene         Sulphuric  acid 

\OH 

Benzene  sulphonic 
acid 

Benzene  sulphonic  acid  reacts  with  alcohols  to  form  esters  : 
C6H5—  SO2—  OH  +  HOR  =  C6H5—  S02-OR  +  H2O 

When  subjected  to  the  action  of  vigorous  reducing  agents 
it  is  reduced  to  phenyl  mercaptan  : 

C6H5—  SO3H  +  6  H  =  C6H5SH  +  3  H20 

The  hydroxyl  of  benzene  sulphonic  acid  is  replaced 
by  chlorine  when  acted  upon  by  phosphorus  pentachloride, 
forming  benzene  sulphonyl  chloride  : 

C6H5S02—  OH  +  PC15  =  C6H5—  SO2—  Cl  +  POC13  +  HC1 


The  Aromatic  Compounds  365 

The  salts  of  benzene  sulphonic  acid  when  fused  with 
sodium  hydroxide  are  decomposed  into  the  metallic  de- 
rivative of  phenyl  alcohol  or  phenol  : 

C6H5—  S03H  +  2  NaOH  =  C6H6ONa  +  NaaSQ,  +  H20 


179.  Phenol,  or  carbolic  acid,  is  obtained  by  the 
action  of  acids  on  the  sodium  phenolate  produced  by 
the  decomposition  of  benzene  sulphonic  acid  by  fu- 
sion with  alkalies. 


HC1  =  +  NaCl 


Sodium  phenate  Phenol 

Phenol  is  present  in  coal  tar  and  is  obtained  in  the  dis- 
tillation of  the  latter.  It  is  separated  from  hydrocarbons 
and  basic  compounds  by  the  solubility  of  its  sodium  com- 
pound in  water.  Sodium  phenolate  or  phenate  is  readily 
formed  in  aqueous  solutions  of  sodium  hydroxide.  In 
this  respect  phenol  shows  properties  markedly  different 
from  the  alcohols  of  the  aliphatic  series.  These  are 
neutral  in  reaction  and  form  metallic  derivatives,  the 
alcoholates,  only  in  non-aqueous  solutions  and  with  the 
alkali  metals.  Phenol,  while  chemically  a  tertiary  alco- 
hol, has  distinctly  acid  properties.  It  is  not  a  sufficiently 
strong  acid  to  react  with  carbonates,  however,  and  while, 
e.g.,  sodium  phenolate  is  stable  to  water,  it  is  decomposed 
by  carbon  dioxide. 

As  an  alcohol  phenol  forms  esters,  but  these  are  not 
readily  formed  by  the  direct  heating  of  phenol  with  an 


366     Organic  Chemistry  for  Students  of  Medicine 

acid.     They  are   easily  formed   by  the  action   of   acid 
chlorides  upon  phenol  or  its  salts : 


CH3—  CO—  Cl=  +HC1 

Acetyl  chloride 


Phenol  Phenol  acetate 

180.  Phenol  Sulphuric  Acid,  also  called  phenyl  sul- 
phuric acid,  is  formed  in  the  animal  body  by  the  union 
of  phenol  with  sulphuric  acid.  Since  phenol  is  a  product 
of  the  putrefaction  of  proteins  by  bacteria  in  the  intes- 
tine, it  is  regularly  absorbed  to  some  extent.  Phenyl 
sulphuric  acid  is  therefore  a  regular  constituent  of  the 
urine,  and  its  amount  depends  upon  the  extent  to  which 
putrefaction  goes  on  in  the  alimentary  canal  : 


+H20 


181.  Phenol  Sulphonic  Acids.  On  dissolving  phenol 
in  concentrated  sulphuric  acid  the  sulphonic  acid  group 
is  readily  introduced  into  the  benzene  nucleus  and  phenol 
sulphonic  acids  are  formed.  The  o-  and  p-  derivatives 
are  thus  obtained.  When  two  sulphonyl  groups  are 
introduced  into  benzene  they  take  the  meta  position  and 
on  fusion  with  potassium  hydroxide  one  is  replaced  by 
hydroxyl,  forming  m-phenol  sulphonic  acid. 


The  Aromatic  Compounds  367 

182.  Phenol  Ethers.  Phenol  also  forms  ethers,  but 
not  readily  by  the  direct  action  of  phenol  with  an  alcohol. 
They  are  easily  produced  by  the  action  of  alkyl  iodides 
upon  the  phenolates  (also  called  phenates) : 


+  CH.I  = 


Phenol  when  pure  is  a  colorless  crystalline  compound 
which  is  very  deliquescent  and  turns  pink  on  contact  with 
the  light  and  air.  It  is  volatile  with  steam,  melts  at 
42°,  and  boils  at  182°.  Its  specific  gravity  at  0  is  1.084°. 
Its  odor  is  characteristic,  and  it  is  highly  toxic  and  cor- 
rosive, the  latter  action  being  due  to  its  great  affinity 
for  water.  One  part  of  phenol  dissolves  in  fifteen  parts  of 
water.  It  is  much  more  soluble  in  alcohol.  It  is  an  excel- 
lent antiseptic. 

Phenol  can  be  formed  by  the  direct  oxidation  of  benzene 
in  the  presence  of  palladium  black  or  aluminum  chloride. 

Like  aniline,  phenol  is  readily  brominated.  When 
bromine  water  is  added  to  a  solution  of  phenol,  symmetri- 
cal tribrom  phenol,  a  very  insoluble  compound,  crystallizes 
out.  This  compound  has  served  for  the  quantitative 
estimation  of  phenol.  Phenol  in  water  gives  a  violet 
coloration  on  adding  a  few  drops  of  a  solution  of  ferric 
chloride. 

/CH3 

183.   Cresols,  C6H4\         .    There  are  three  homologues 

X)H 
of  phenol,  the  o-,  m-,  and  p-,  methyl  phenols  or  cresols. 


368     Organic  Chemistry  for  Students  of  Medicine 

They  all  occur  in  the  distillate  from  coal  tar.  They 
possess  antiseptic  properties  and  are  much  employed  in 
disinfection.  When  pure  they  are  crystalline  solids, 
o-cresol  melts  at  31°,  the  m-  and  p-cresols  at  5°  and 
36°  respectively.  Like  phenol  they  give  a  coloration 
with  ferric  chloride  and  are  readily  brominated  and 
nitrated. 

184.  Picric   Acid.     Nitric   acid   acts   energetically   on 
phenol,   forming  symmetrical    trinitro  phenol,   or  picric 
acid.    The  latter  compound  is  also  formed  by  the  ac- 
tion of  nitric  acid  upon  various  substances  containing 
proteins,  since  the  phenyl  and  phenol  groups  are  con- 
tained in  two  of  the  amino  acids  found  in  nature,  viz. 
phenyl  alanine  and  tyrosine.      Picric  acid   is   a   bright 
yellow  crystalline  substance  of  strongly  acid  character. 
The   introduction   of   negative   groups,  as  halogens,  or 
nitro  groups,  into  phenol  increases  its  acid  character, 
while  the   introduction   of   basic   groups,    as    NH^,  de- 
presses the  acid  character. 

Picric  acid  forms  readily  crystallizing  salts  of  slight 
solubility  with  many  natural  bases  and  is  of  great  impor- 
tance in  the  isolation  and  purification  of  these.  It  melts 
at  122°  and  can  be  sublimed  without  decomposition, 
but  is  explosive,  owing  to  the  large  amount  of  oxygen 
contained  within  its  molecule,  which  makes  possible  its 
complete  and  sudden  self-oxidation.  The  salts  of  picric 
acid  are  much  more  explosive,  decomposing  with  violence 
when  heated  or  struck. 

185.  Tyrosine,  a-amino,  /3-oxyphenyl  propionic   acid, 
or  par  a-oxy  phenyl  alanine: 


The  Aromatic  Compounds  369 

OH 


CH2— CH— COOH 

NH2 

is  a  constituent  of  many  proteins,  and  was  first  isolated  by 
Liebig  in  1846.  It  is  set  free  from  its  union  with  other 
amino  acids  during  the  digestion  of  the  proteins,  and  is 
also  formed  by  boiling  proteins  with  mineral  acids.  It  is 
not  present  in  gelatin,  and  the  best  yield  is  obtained  from 
the  hydrolysis  of  silk.  With  the  other  amino  acids  it  is 
always  present  in  the  blood  in  minute  amounts.  Tyrosine 
is  a  colorless  compound  forming  long  silky  needles  which 
are  but  slightly  soluble  in  cold  water,  but  more  easily  in 
hot.  Dilute  acids  or  alkalies  dissolve  it,  and  on  neutraliz- 
ing the  solutions,  it  crystallizes  out.  It  gives  a  red  color 
with  a  solution  of  mercuric  nitrate  in  nitric  acid,  containing 
some  nitrous  acid.  This  is  the  Millons  reaction,  which 
has  long  served  as  a  qualitative  test  for  proteins.  Gela- 
tin when  pure  does  not  respond  to  this  test.  This  color 
reaction  is  also  given  by  phenol  and  other  phenyl  deriva- 
tives containing  a  hydroxyl  group  attached  to  the  benzene 
nucleus. 

Tyrosine  is  apparently  one  of  the  amino  acids  which  is 
indispensable  from  the  diet.  On  being  acted  upon  by 
anaerobic  bacteria  the  alanine  complex  is  removed  and 
phenol  formed.  Tyrosine  is  the  source  of  the  phenol 

2B 


370     Organic  Chemistry  for  Students  of  Medicine 


formed    by   putrefactive    action   in   the    intestine.     The 
transformation's  involved  are  illustrated  by  the  following : 

OH  OH  OH 

-CO2 


CH2—  CH2—  COOH  CH2—  CH—  COOH  CH2—  CH2NH2 

p-oxyphenyl-  Tyramine 

propionic  acid  IT-TT  p-oxyphenyl- 

ethylamine 


Tyrosine 

a-amino-/3-oxyphenyl- 
propionic  acid 


+  3O 


Phenol 

CH2—  COOH 

p-oxyphenyl-acetic 
acid 

These  changes  are  the  result  of  the  power  of  bacteria 
to  remove  CO2  from  the  carboxyl  group  in  a  manner 
analogous  to  that  of  the  enzyme  carboxylase  on  pyruvic 
acid  ;  to  remove  the  amino  group  from  amino  acids  as 
ammonia;  and  to  oxidize  aliphatic  side  chains. 


186.   Tyramine  ,  C6H4<  ,  or  p-oxyphe- 

XCH2—  CH2—  NH2 

nyl-ethylamine,  is  a  substance  of  mild  toxicity  occurring 
in  putrefaction  mixtures.     Doses  of  1-2  mg.  injected  intra- 


The  Aromatic  Compounds  371 

venously  cause  a  sudden  and  pronounced  rise  in  blood 
pressure  which  soon  passes  away.  The  absorption  of  this 
compound  from  the  intestine  is  possibly  in  part  respon- 
sible for  high  blood  pressure  in  certain  individuals. 

187.   Dihydroxy  Benzenes. — The  three  dihydroxy  ben- 
zenes occur  among  natural  products : 

OH  OH  OH 

iOH 


Ortho- 
Pyrocatechin  ___________ 

or  catechol  Para- 

Hydroquinone  or  qumol 


188.  Pyrocatechin,  o-dihydroxy  benzene,  CeH^OH^,  is 
obtained  by  fusing  o-phenol  sulphonic  acid  with  potassium 
hydroxide  : 

OH  OH 

i—  S03H+KOH 

KHSO3 


It  is  a  colorless  crystalline  compound  melting  at  104°. 
It  occurs  in  the  resin  catechu  and  in  beech  wood  tar. 

189.  Guiacol  and  Veratrol  are  the  monomethyl  and 
the  dimethyl  ethers  respectively  of  pyrocatechin. 

OH  OCH3 


u       u 

Guiacol  Veratrol 


372     Organic  Chemistry  for  Students  of  Medicine 

The  former  is  found  in  beech  wood  tar  and  the  latter  in 
the  seeds  of  Sabadilla  officinalis. 

190.  Resorcinol,   m-dihydroxy   benzene,   C6H4(OH)2,   is 
obtained    from   benzene  m-disulphonic    acid    by  fusion 
with  potassium  hydroxide  at  high  temperatures.     It  is  a 
colorless  crystalline  compound  which  melts  at  119°  and 
is  somewhat  volatile  with  steam.     It  has  not  been  found 
in  nature,  but  results  from  the  fusion  of  various  plant 
tissues    with    alkali.     Its    homologue,  methyl    resorcinol 
orcin  (m-dihydroxy  toluene),  occurs  in  certain  mosses. 

Resorcinol  is  largely  used  for  the  preparation  of  the  dye 
eosin. 

191.  Hydroquinone,    p-dihydroxy   benzene,    CeH^OH^ 
occurs  as  a  glucoside  arbutin  which  is  widely  distributed  in 
plants  of  the  family  Ericaceae.     It  is  crystalline  and  melts 
at  170°.     It  is  difficultly  soluble  in  the  ordinary  solvents. 

192.  Quinone  is  formed  by  the  oxidation  of  aniline 

CO 

/\ 
HC      CH 


HC      CH 

\/ 
CO 

with  chromic  acid.  It  is  an  evil-smelling  substance, 
easily  volatile  with  steam.  Easily  soluble  in  hot  water 
and  in  organic  solvents.  It  is  converted  into  hydro- 
quinone  on  reduction.  Quinone  forms  golden  yellow 
crystals  which  melt  at  116°. 


The  Aromatic  Compounds  373 

TRIHYDROXY   BENZENES 

193.  Pyrogallol:   l,2,3trihydroxy  benzene,  C6H3(OH)3, 
is  formed  by  the  distillation  of  gallic  acid  (212). 

C6H2(OH)3— COOH  =  C6H3(OH)3  +CO2 

Its  alkali  salts  absorb  oxygen  readily,  and  its  solution 
in  sodium  hydroxide  is  employed  in  gas  analysis  for  this 
purpose.  The  compound  is  oxidized  and  carbon  monoxide 
is  liberated  as  one  of  the  decomposition  products.  It  is 
employed  as  a  developer  in  photography. 

194.  Phloroglucin,  1,3,5  trihydroxy  benzene,  C6H3(OH)3, 
is  prepared  by  the  oxidation  of  resorcinol.      It    crys- 
tallizes from  water,   and    melts    at   217°.      It   gives    a 
blue  violet  color  with  ferric  chloride. 

195.  Inosite,  CeH^Oe,  occurs  in  nature  in  several  isomeric 
forms.     It  is  a  derivative  of  the  reduced  benzene  ring, 
hexamethylene,  and  is  hexahydroxy  benzene : 

CHOH 

HOHC   CHOH 

I   I 
HOHC   CHOH 

V 
CHOH 

Inosite  is  found  in  heart  muscle,  in  the  brain,  and  is 
widely  distributed  in  plants,  especially  in  beans  and  peas 
in  the  unripe  state.  Its  hexaphosphoric  acid  ester  is 
called  phytic  acid,  and  is  present  in  considerable  amount 
in  wheat  bran  and  is  a  common  constituent  of  plants. 


374     Organic  Chemistry  for  Students  of  Medicine 

196.   Thymol   and   Carvacrol   are   naturally   occurring 
methyl-isopropyl  phenols.    They  are  derivatives  of  cymene. 


CH 

/\ 
CH3   CH3 

Carvacrol 

Thymol  and  carvacrol  are  found  in  many  plants. 
They  have  a  very  pleasant  mint-like  odor  and  possess 
mild  antiseptic  action. 

197.  Protocatechuic  Acid,  catechol  carboxylic  acid,  re- 
sults from  the  fusion  of  many  resins  with  alkali.     It  is 
readily  soluble  in  water  and  melts  at  199°. 

198.  Veratric  Acid,  Vanillin,  and  Coniferyl  Alcohol.  — 


COOH  COOH  CH  =  CH— CH2OH 

Veratric  acid  Vanillin  Coniferyl  alcohol 

Veratric  acid,  the  dimethyl  ester  of  protocatechuic  acid, 
occurs  in  the  seeds  of  Vemtrum  Sabadilla. 

Vanillin  is  the  substance  giving  the  pleasant  odor  to 


The  Aromatic  Compounds  375 

the  vanilla  bean.     It  is  obtained  by  the  oxidation  of 
coniferyl  alcohol. 

Coniferyl  alcohol  occurs  in  coniferin,  a  glucoside  found 
in  the  cambium  sap  of  all  coniferse  and  in  other  plants. 

0-C6Hn06 


CH=CH— CH2OH 

Coniferin  (glucoside) 

199.  Homogentisic,  quinol  acetic  acid,  is  a  constituent 
of  the  urine  in  a  type  of  abnormal  metabolism  known  as 
alkaptonuria.  The  normal  animal  body  is  capable  of 
the  complete  oxidation  of  the  benzene  ring  when  it  is 
introduced  in  the  form  of  tyrosine  or  phenyl  alanine, 
but  there  is  an  anomaly  of  metabolism  in  which  the  later 
steps  in  the  process  fail.  The  mode  of  formation  of  homo- 
gentisic  acid  from  tyrosine  is  probably  as  follows : 
OH  OH  OH 


CH 


V^J-J-X  1 

C001 


CHNH2  -NH3          CO        +O          COOH 

—  Pn,       Homogenize 
V^W2  acid 

)H  COOH 

Tyrosine  p-oxyphenyl- 

pyruvic  acid 


376     Organic  Chemistry  for  Students  of  Medicine 


200.  Adrenin, 


CHOH 


CH2 


— NH— CH3 

is  the  active  principle  of  the  adrenal  glands,  and  one  of 
the.  endogenous  hormones,  i.e.  chemical  regulators  of 
metabolism.  It  has  been  produced  synthetically  by  the 
following  reactions : 

OH  OH 

,OH 


H 
HO 


OC— CH2C1 


CatechoI+Ghloracetic  acid 

OH 
i  OH 


CH2C1  +  HNHCH3 

Chloraceto-catechol+Methyl  amine 

OH 
OH 


+  2H 


CH2— NH— CH3 

Methyl-amino-aceto-catechol 


CHOH 


CH2— NH— CH3 

Adrenin 


The  Aromatic  Compounds  377 

The  synthetic  product  is  optically  inactive,  but  has 
been  resolved  into  its  optical  components.  The  natural 
product  is  levorotatory  and  greatly  surpasses  the  dextro 
form  in  physiological  activity.  Adrenin  produces  a 
marked  rise  of  blood  pressure  through  a  constriction  of 
the  blood  vessels. 

201.  Benzole  Acid,  C6H5COOH,  is  formed  by  the  oxi- 
dation of  toluol  and  its  homologues  containing  longer 
side  chains.  It  is  found  in  gum  benzoin,  and  other  resins. 
In  gum  benzoin  it  is  present  chiefly  as  its  ester,  with 
benzyl  alcohol  as  benzoate.  It  occurs  also  in  cranberries. 

Benzoic  acid  is  formed  from  benzotrichloride  by  boil- 
ing with  water.  The  behavior  of  the  three  chlor  toluenes 
in  which  the  chlorine  is  in  the  side  chain,  when  boiled  with 
water,  is  of  synthetic  interest: 

C6H5-CH2C1  +  HOH     =  C6H5-CH2OH  +  HC1 

Benzyl  chloride  Benzyl  alcohol 

C6H5— CHC12  +  2  HOH  =  C6H5— CHO  +  2  HC1 

Benzal  chloride  Benzaldehyde 

C6H5— CC13  +  3  HOH     =  C6H5— COOH  +  3  HC1 

Benzotrichloride  Benzoic  acid 

Benzoic  acid  results  from  the  oxidation  of  either  benzal- 
dehyde  or  of  benzyl  alcohol  with  benzaldehyde  as  an  inter- 
mediate product.  The  acid  can  also  be  formed  by  the 
hydrolysis  of  phenyl  nitrile  (177). 

Benzoic  acid  has  all  the  ordinary  properties  of  an  acid, 
forming  salts,  esters,  etc.  It  is  a  colorless  crystalline 
compound  which  is  fairly  readily  soluble  in  hot  water, 
but  very  slightly  soluble  in  cold  (1  part  in  400). 


378     Organic  Chemistry  for  Students  of  Medicine 

Physiological  Properties.  Benzoic  acid  has  very  little 
toxicity,  large  doses  not  being  followed  by  any  appreciable 
effects.  Within  the  tissues  it  undergoes  conjugation  with 
glycocoll  to  form  hippuric  acid: 


CO  |OH+     H|  HN— CH2— COOH 


CO^-NH—  CH2—  COOH  +  H2O 

Hippuric  acid  (benzoyl-glycocoll) 

Saccharin  is  a  derivative  of  o-sulphobenzoic  acid,  which 
is  of  particular  interest  because  of  its  extreme  sweetness. 
It  is  about  500  times  sweeter  than  cane  sugar,  and  has 
been  employed  to  a  considerable  extent  as  an  adulterant 
of  foodstuffs  in  place  of  sugar,  which  is  more  expensive. 
The  following  reactions  show  the  method  of  synthesis  : 


/CH3 

^  —  >  CeH^ 

\SO3H  \SO2C1 

CH3  /COOH  CO 


C6H  -e  - 

\SO2NH2  \S02NH2        C6H4         NH 


S02 

Saccharin 

202.  Hippuric  Acid  (201)  is  normally  found  in  very  small 
amount  in  the  urine  especially  of  the  herbivora.  It  is 
not,  however,  a  product  of  metabolism,  but  is  present 
there  because  the  foodstuffs  of  the  herbivorous  animal, 


The  Aromatic  Compounds  379 

and  to  a  less  extent  of  the  omnivora,  contain  substances 
which  are  oxidized  to  benzoic  acid  in  the  tissues. 

Hippuric  acid  is  not  very  soluble  in  cold  water  and  less 
so  in  hydrochloric  acid ;  and  if  much  is  present  in  the  urine, 
it  will  crystallize  out  on  acidifying  with  hydrochloric 
acid  or  better  with  the  addition  of  ammonium  sulphate. 
Glycocoll  therefore  serves  as  a  protective  substance 
against  the  foreign  substance,  benzoic  acid. 

203.  Benzyl  Alcohol,  C6H6CH2OH,  occurs  as  such  and 
also  in  ester  combination  with  benzoic  and  cinnamic  acid 
(207),  in  Tolu  balsam,  Peru  balsam,  and  in  the  resin  storax. 
It  is  isomeric  with  the  cresols  (183).    Benzyl  alcohol  is 
formed  by  the  method  described  in  (201),  and  by  the 
reduction  of  benzaldehyde.     It  is  a  liquid  which  boils 
at  206°,  sparingly  soluble  in  water,  but  more  readily  in 
alcohol  and  ether.     It  has  all  the  typical  properties  of  the 
alcohols. 

204.  Benzaldehyde,  C6H5CHO,  is  found  in  the  gluco- 
side  amygdalin  from  bitter  almonds,  where  it  is  in  union 
with  two  molecules  of  glucose  and  one  of  hydrocyanic  acid. 

For  its  preparation  from  benzal  chloride  see  (201). 
It  is  a  colorless  liquid  with  the  odor  of  bitter  almonds.  It 
boils  at  179°,  is  very  slightly  soluble  in  water,  but  readily 
in  alcohol  and  ether.  It  behaves  in  most  respects  like 
the  aliphatic  aldehydes,  but  differs,  from  these  in  the  fol- 
lowing respects : 

It  does  not  reduce  Fehling's  solution  or  ammoniacal 
silver  solutions.  It  does  not  polymerize,  and  when  heated 
with  alkalies  one  molecule  is  reduced  to  benzaldehyde  and 
another  is  simultaneously  oxidized  to  benzoic  acid  (p.  61). 


380     Organic  Chemistry  for  Students  of  Medicine 

On  shaking  an  alcholic  solution  of  benzaldehyde  with 
potassium  cyanide  two  molecules  condense  to  form  the 
ketone  alcohol  benzoin.  Benzaldehyde  yields  nitro 
derivatives,  sulphonic  acids,  etc.  o-nitrobenzaldehyde 
condenses  with  acetone  to  form  indigo  blue. 

PHENYL   FATTY   ACIDS 

205.  Phenyl  Acetic  Acid  is  formed  in  small  amounts  in 
putrefaction  of  proteins.     It  is  closely  related  to  mandelic 
acid,  the  nitrile  of  which  occurs  in  amygdalin: 

C6H5CH2— COOH  C6H5CHOH— COOH 

Phenylac»tic  acid  Mandelic  acid 

Its  nitrile  is  formed  from  benzyl  chloride  by  the  action 
of  potassium  cyanide : 

C6H5CH2C1 +KCN  =C6H5CH2CN  +KC1 

206.  Phenyl    Amino    Propionic    Acid,    C6H5— CH2— 
CH — COOH,  or  phenyl  alanine,  is  a  constant  constituent 

NH2 

of   proteins.     On   putrefaction   it   gives   rise   to   phenyl 
propionic  acid : 

C6H5— CH2— CH— COOH  +  2  H 

NH2 

=  C6H5— CH2— CH2— COOH+NH3 

Phenyl  alanine  is  not  readily  isolated  from  among  the 
products  of  hydrolysis  of  proteins.  The  form  which 
occurs  in  nature  is  levorotatory.  It  is  crystalline  and 
melts  at  275-280°. 


The  Aromatic  Compounds  381 

207.  Cinnamic  Acid,  C6H5— CH  =  CH— COOH,  phe- 
nyl  acrylic  acid,  is  found  in  the  resin  storax.  It  is  the 
most  important  phenyl  derivative  containing  an  un- 
saturated  side  chain.  A  synthesis  described  by  Per- 
kin  is  of  unusual  interest.  Benzaldehyde  condenses  with 
sodium  acetate  when  the  two  are  heated  together  in  the 
presence  of  a  dehydrating  agent  (acetic  anhydride). 


C6H5— CH|0+H2|  CH— COONa 

Benzaldehyde  Sodium  acetate 

=  C6H5— CH  =  CH— COONa 

Alcohol,  aldehyde  and  acid  derivatives  of  phenol  are  also 
found  in  nature.  The  first  of  these  is  represented  by  salig- 
enin,  which  occurs  in  the  glucoside  salicin  in  willow  bark. 
It  is  a  crystalline  solid  easily  soluble  in  water  and  melting 
at  82°.  The  phenol  group  is  in  the  ortho  position. 

/OH 

208.  Salicylic    Aldehyde,    C6H/  .    The  ortho- 

\CHO 

compound  is  found  in  certain  volatile  oils. 

/OH 

209.  Salicylic  Acids.  — C6H/  .     The  ortho- com- 

\COOH 

pound  is  of  greatest  importance.  It  occurs  as  the  methyl 
ester  in  oil  of  wintergreen,  and  the  acid  is  likewise  found  in 
the  flowers  of  Spiraea. 

210.  Aspirin  is  acetyl  salicylic  acid : 

/OH  /O.OC— CH3 

C6H/  +  CH3— COC1  =  C6H/ 

\COOH        Acetyl  chloride  \COOH 

Salicylic  acid  Acetyl  salicylic  acid 


382     Organic  Chemistry  for  Students  of  Medicine 

211.  Salol  is  phenyl  salicylate  : 

/OH 
C6H/ 

\COOC6H5 

OH 

HO 

212.  Gallic  Acid,  ,  is  found  in  many 


plants,  as  gall  nuts,  tea,  etc.     It  is  formed  when  tannin  is 
hydrolyzed.     It  is  a  crystalline  compound  melting  at  220°. 
It  gives  the  same  reaction  with  ferric  chloride  as  does 
pyrogallol. 
213.   Tannic  Acid,  or  digallic  acid, 


OH 
OH 

Tannic  acid 

is  an  ester  formed  between  two  molecules  of  gallic  acid. 
It  occurs  in  gall  nuts,  sumach,  and  other  barks. 

214.  Tannins  are  of  several  varieties,  distinguished  by 
the  color  reactions  which  they  give  with  various  reagents. 
There  are  distinguished  two  general  classes,  the  pyrogallol 
and  the  catechol  varieties.  The  former  give  a  dark  blue 
color  with  ferric  salts  (ink)  and  the  latter  a  greenish  black. 
The  latter  forms  a  dark  red  ring  at  the  juncture  of  the 
liquids  when  its  solutions  are  treated  with  concentrated 
sulphuric  acid. 


The  Aromatic  Compounds  383 

Tannin  on  hydrolysis  yields  7-8  per  cent  of  glucose,  and 
gallic  acid.  Its  constitution  has  not  been  determined  with 
certainty,  but  it  is  in  some  samples  the  penta  digallic 
ester  of  glucose : 

CH2O— t 

I 
CHO— t 


t  represents  digallic  or  tannic  acid  in  this  formula.  One 
of  the  tannins  recently  synthesized  by  Fischer  has  nearly 
double  the  molecular  weight  of  the  most  highly  complex 
compound  hitherto  synthesized. 


CHAPTER  XVIII 
CONDENSED   BENZENE   RINGS 

215.  Naphthalene,  CioH8,  is  present  in  considerable 
amount  in  coal  tar.  Its  structure  is  made  clear  by  the 
behavior  of  its  nitro  and  amino  derivatives  on  oxidation. 
Naphthalene  on  oxidation  yields  phthalic  acid  (171), 
which  shows  that  it  contains  a  benzene  nucleus  and  two 
substituting  groups  in  the  ortho  position.  On  oxidizing 
the  nitro  compound,  nitrophthalic  acid  is  formed.  When 
the  nitro  group  is  reduced  to  an  amino  group  and  the 
naphthyl  amine  oxidized,  phthalic  acid  is  formed.  The 
molecule  must  therefore  consist  of  two  benzene  rings  hav- 
ing two  carbon  atoms  in  common  : 


NO2 

Nitrophthalic  acid        Amino  naphthalene 

384 


Phthalic  acid 


Condensed  Benzene  Rings  385 

Naphthalene  derivatives  are  extensively  employed  in 
the  manufacture  of  dyes. 

Naphthalene  yields  two  mono  substitution  products 
a-  and  - : 


216.  Anthracene,  C^Hio,  is  formed  by  the  Fittig  synthe- 
sis from  o-brom  benzyl  bromide,  with  subsequent  oxida- 
tion: 


o 


|Br         +2Na     Br|  H2C- 

— CH2|Br+2Na  Br" 

CH2 


-2H  = 

+j 

CH2 


Anthracene 


The  structure  of  an  anthracene  derivative  is  arrived  at 
through  a  study  of  the  structure  of  its  simpler  oxidation 
products. 

Anthracene  is  a  constituent  of  coal  tar,  and  is  the  mother 
substance  of  the  red  dye  derived  from  the  madder  root. 
It  is  a  colorless  crystalline  solid  with  a  blue  fluorescence, 
which  melts  at  213°  and  boils  at  351°.  It  is  easily  soluble 
in  benzene  but  difficultly  in  water,  alcohol,  and  ether. 
2c 


386     Organic  Chemistry  for  Students  of  Medicine 

Nitric  acid  oxidizes  anthracene  to  anthraquinone,  a  pale 

CO 


CO 

Anthraquinone 

yellow  crystalline  substance  with  the  nature  of  a  ketone. 
It  is  used  in  making  the  dye  alizerin. 


CHAPTER   XIX 
ALIZERINE -DYES 

217.  Alizerine  occurs  in  the  madder  root  in  the  form  of  a 
glucoside,  ruberythric  acid.  It  is  hydrolyzed  by  an  enzyme 
in  the  plant  or  by  dilute  acids,  forming  glucose  and  the 
dye  "  Turkey  red."  It  is  now  made  from  anthraquinone. 
Its  structure  is : » 

CO  OH 

lOH 


The  hydroxyl  groups  are  introduced  by  first  making  the 
sulphonic  acid  derivative  by  the  direct  action  of  H2SO4 
and  then  heating  with  sodium  hydroxide  (178). 
Other  alizerine  dyes  are  : 


O    OH 


HO 


CO 

Purpurin 


OH 


CO 

Anthropurpurin 


387 


388     Organic  Chemistry  for  Students  of  Medicine 


10   OH 


CO 

Flavopurpurin 

Only  those  phenol  derivatives  of  anthracene  containing 
two  hydroxyls  in  the  ortho  position  to  each  other  are  dyes. 

THE   TRIPHENYL   METHANE    DYES 

218.  Malachite  Green  is  formed  by  heating  benzalde- 
hyde  with  dimethyl  aniline  and  a  dehydrating  agent 
(ZnCl2). 


Benzaldehyde 


=  C6H5— CH 

C6H4— N(CH3)2 

Malachite  green 

It  is  an  excellent  dye  for  silk  and  wool,  but  for  dyeing 
cotton  a  mordant  is  required. 

Brilliant  Green  is  prepared  in  the  same  way  as  is  mala- 
chite green,  but  diethyl  aniline  is  employed. 

Acid  Green  is  also  analogous  to  malachite  green  except 
that  ethylbenzylaniline  is  employed. 

Pararosaniline  is  prepared  from  p-toluidine  and  aniline 
by  the  action  of  an  oxidizing  agent : 


Alizerin  Dyes 


389 


H2N 


6H4— NH2 
6H4— NH2 

p-rosaniline 

Rosaniline,  fuchsine,  or  magenta,  is  prepared  from  a  mix- 
ture of  p-toluidine,  o-toluidine,  and  aniline  in  an  analogous 
manner. 

Rosaniline  and  pararosaniline  are  reddish-blue  dyes  and 
can  be  converted  into  dyes  having  a  bluer  tint  by  methyla- 
tion  with  methyl  iodide  (176). 

Ethylation  of  the  amino  groups  forms  deeper  blue  dyes, 
while  phenylation  forms  a  pure  blue  dye  known  as  aniline 
blue. 

Phenolphthalein  is  another  triphenyl  methane  derivative 
formed  from  phenol  and  phthalic  anhydride : 


II 


Phthalic  anhydride 


-C6H4OH 
C6H4OH 


0 

Phenolphthalein 


390    Organic  Chemistry  for  Students  of  Medicine 

Fluorescein,  eosin,  erythrosin,  and  many  other  dyes 
are  derivatives  of  triphenyl  methane. 

THE    AZO   DYES 

219.  By  substituting  the  hydroxyl  of  diazo-benzene 
(177)  by  amines,  phenols,  etc.,  a  great  number  of  dyes  of 
both  basic  (from  amines)  and  acid  (from  phenols)  charac- 
ter have  been  produced : 

C6H5— N  =  N— OH  +  H/       ~\— NH2 

=  C6H5— N  =  N— C6H4— NH2 

C6H5— N  =  N— OH+  H<^     ^>— OH 

•|         =  C6H5— N  =  N— C6H4— OH 

Congo  red,  bismarck  brown,  chrysoidin,  helianthin, 
resorcin  yellow,  belong  to  this  class. 


CHAPTER   XX 
HETEROCYCLIC    COMPOUNDS 

220.  Pyrrole,  pyrimidines,  and  imidazoles  have  been 
already  described  as  representing  compounds  of  cyclic 
structure  in  which  both  carbon  and  nitrogen  were  present. 
It  remains  to  describe  the  six-membered  ring  containing 
five  carbon  atoms  and  one  nitrogen.  The  simplest  mem- 
ber of  this  group  is  pyridine.  Neither  pyridine  nor  its 
derivatives  play  a  role  in  the  biological  processes  of  ani- 
mal life  as  do  the  heterocyclic  compounds  mentioned 
above,  but  it  is  found  widely  distributed  in  plants,  espe- 
cially in  the  alkaloids.  Pyridine  itself  is  a  highly  toxic 
substance.  It  is  represented  as  follows: 

CH 

HC     CH 

II      I 
HC     CH 

\s 

N 

Its  structure  is  arrived  at  by  a  method  for  its  formation. 
Pentamethylene  diamine  (74)  hydrochloride  on  dry  dis- 
tillation loses  a  molecule  of  ammonium  chloride  with  the 
formation  of  the  reduced  cyclic  structure  piperidine  which 
on  oxidation  yields  pyridine  : 

391 


392     Organic  Chemistry  for  Students  of  Medicine 

CH2 

/\ 
H2C      CH2 


CH, . 

:H2— CH2-JNH2HC1|     HC     CH2 

Pentamethylene-diamine  hydrochloride  \/ 

NH 

Piperidine 


CH 

HC     CH 

II       I 
HC     CH 


N 

Pyridine 

Pyridine  and  certain  of  its  homologues  are  present  in  coal 
tar,  and  in  "  Dippel's  Oil,"  the  foul-smelling  product  of  the 
dry  distillation  of  bones. 

Pyridine  is  a  colorless  liquid  with  the  odor  of  tobacco 
smoke.  It  is  a  strongly  alkaline  substance  which  mixes 
with  water  in  all  proportions.  It  boils  at  115°.  It  is 
one  of  the  most  stable  of  organic  substances,  being 
unattacked  by  boiling  nitric  or  chromic  acid.  With 
sulphuric  acid  it  reacts,  forming  a  sulphonic  acid. 
Halogens  scarcely  attack  it.  On  heating  pyridine  with 
hydriodic  acid  at  300°  it  is  destroyed,  yielding  normal 
pentane  and  ammonia. 

Pyridine  forms  salts  with  acids.  It  does  not  form  a 
nitroso  derivative  with  nitrous  acid. 

As  a  tertiary  amine  pyridine  combines  with  alkyl  halides. 
These  show  an  interesting  rearrangement  when  heated, 


Heterocyclic  Compounds  393 

the  alkyl  group  changing  its  position  from  the  nitrogen  to 
the  a-carbon  atom. 


CH3I  = 

V        ^ 

N 

a-methyl  pyridine 

CH3   I 

Pyridine  methiodide 

A  delicate  test  for  pyridine  consists  in  heating  the  sub- 
stance to  be  tested  with  a  few  drops  of  methyl  iodide,  then 
adding  a  small  quantity  of  solid  potassium  hydroxide  and 
heating  again.  Methyl  pyridine  hydroxide,  having  an 
extremely  disagreeable  odor,  is  formed  when  pyridine  is 
present. 

Piperidine,  C5Hi0NH,  is  formed  by  heating  the  hydro- 
chloride  of  pentamethylene  diamine  (74)  or  by  the  reduc- 
tion of  pyridine  with  sodium  and  alcohol.  It  behaves  like 
a  secondary  amine  in  forming  a  nitroso  derivative  when 
treated  with  nitrous  acid. 

Piperidine  occurs  as  a  constituent  of  the  alkaloid  piperine 
found  in  pepper.  It  is  a  strong  base,  which  boils  at  106°. 

HOMOLOGUES   OF   PYRIDINE 

The  methyl  pyridines  are  known  as  picolines;  the  di- 
methyl pyridines,  as  lutidines;  and  the  trimethyl  pyridines, 
as  collidines.  Their  properties  are  closely  similar  to  those 
of  pyridine. 

221.   Nicotinic  Acid  is  the  /3-pyridine  carboxylic  acid  •; 


394     Organic  Chemistry  for  Students  of  Medicine 

COOH 


rCOOH 


COOH 


N  N  N 

Picolinic  acid  Nicotinic  acid  Isonicotinic  acid 

Nicotinic  acid  is  derived  from  the  alkaloid  nicotine  by 
oxidation. 

Picolinic  acid  is  distinguished  from  the  other  isomeric 
acids  by  its  property  of  giving  a  red  color  with  ferrous 
sulphate. 

Quinolinic  Acid  is  an  a-/3-dicarboxy  pyridine.     At  190° 


N 

Quinolinic  acid 

it  loses  carbon  dioxide  and  is  converted  into  nicotinic  acid. 
222.    Quinoline  is  a  compound  containing  a  benzene  ring 
condensed  with  a  pyridine  ring : 


JN 

Isoquinoline 


Quinoline 


Both  isomers  occur  in  coal  tar,  but  quinoline  is  usually 
prepared  by  synthesis.  Its  structure  is  made  clear  by  its 
synthesis  from  allyl  aniline  by  oxidation : 


Heterocyclic  Compounds 


395 


OHC— CH= CH2 

Allyl  aldehyde 


v    XNH2 

Aniline 

/\ 

CH2 

\ 

CH 

1 

CH 

+  0 


N 


H20 


and  further  by  the  fact  that  quinoline  yields  on  oxidation 
quinolinic  acid : 

/v     /\ 

HOOC 
-> 

HOOC 


It  is  a  colorless  liquid  of  an  oily  consistency  which  boils 
at  239°  and  has  a  characteristic  rather  pleasant  smell. 

Isoquinoline  closely  resembles  quinoline,  but  is  a  solid 
which  melts  at  23°  and  boils  at  241°. 

Both  quinoline  and  isoquinoline  are  constituents  of 
alkaloids. 

INDOLE   AND    ITS    DERIVATIVES 

223.  Indole  is  a  compound  which  contains  a  condensed 
benzene  and  a  pyrole  ring,  the  two  having  two  ortho-  car- 
bon atoms  in  common.  It  is  found  in  coal  tar  and  is  a 
constituent  of  one  of  the  important  amino  acids  contained 


396     Organic  Chemistry  for  Students  of  Medicine 


in  proteins,  o-amino  mandelic  acid  is  converted  by  the 
elimination  of  water  into  dioxindole,  from  which  by  vigor- 
ous reduction  indole  is  formed  : 


— CHOH— CO 


NH[H: 


OH 


o-amino  mandelic  acid 


CHOH 


NH 

Dioxindole 

Indole  is  crystalline  and  melts  at  52°.  It  has  a  fecal-like 
odor,  and  is  volatile  with  steam.  It  is  soluble  in  various 
organic  solvents. 

It  is  the  complex  which  gives  the  red  color  with  sul- 
phuric acid  and  glyoxylic  acid  (Hopkins  and  Cole's  re- 
agent) which  is  characteristic  of  many  proteins. 

224.  Methyl  Indole,  or  Scatole,  is  found  in  putrefaction 
mixtures  and  in  feces,  where  it  results  from  tryptophane, 
one  of  the  amino  acids : 


NH 

Scatole 

225.     Indoxyl  occurs  in  Isatis  tinctoria  as  a  glucoside, 
indican. 


Heterocyclic  Compounds 
—OH 


397 


NH 


This  is  hydrolyzed  by  an  enzyme  in  the  plant  and 
the  free  indoxyl  undergoes  oxidation  to  the  blue  dye 
indigo.  Indoxyl  is  a  product  of  the  putrefaction  of  trypto- 
phane  and  is  formed  in  the  intestine  from  proteins  and 
being  absorbed  is  eliminated  in  the  urine,  principally  as 
indoxyl  sulphuric  acid,  which  is  analogous  to  phenol  sul- 
phuric acid  (180)  in  its  constitution.  The  formation  of 
indigo  is  the  basis  of  the  indican  reaction  of  urine. 
226.  Indigo : 


II         + 

C|H        o 

HjC 

NH 

2  Indoxyl 

/ 

~\/\/ 
NH 

\         rn    nr 

NH  NH 

Indigo  blue 

Indigo  white  is  a  reduction  product  of  indigo  blue : 

:OH  HOC- 


NH 


NH 


Indigo  white 


398     Organic  Chemistry  for  Students  of  Medicine 
227.    Tryptophane,  or  a-amino,  /3-indole  propionic  acid,  is 

:H2— CH— COOH 

NH2 
NH 

a  constituent  of  many  proteins.  It  is  the  complex  which 
gives  Adamkiewic's  reaction  for  proteins  (Hopkins-Cole 
reaction) . 

It  is  a  colorless  crystalline  compound  readily  soluble  in 
hot  water,  but  difficultly  soluble  in  cold.  Insoluble  in 
absolute  alcohol  and  in  ether.  It  is  soluble  in  hot  pyridine. 
It  melts  at  252°  after  becoming  brown  at  240°.  It  is  a 
weak  base  and  forms  salts  with  acids.  Some  of  its  acyl 
derivatives  formed  by  the  action  of  acid  chlorides  are  of 
experimental  value  because  of  their  properties.  Trypto- 
phane is  destroyed  in  the  hydrolysis  of  proteins  by  mineral 
acids,  but  is  stable  to  barium  hydrate. 

Tryptophane  gives  a  red  color  when  a  trace  of  bromine 
is  added  to  its  solutions  acid  with  acetic  acid.  With  con- 
centrated sulphuric  acid  and  glyoxylic  acid  it  gives  a 
reddish  violet  color. 

Persons  suffering  from  melanotic  tumor  excrete  a  pig- 
mented  substance  called  melanin  in  the  urine.  It  has 
been  rendered  highly  probable  that  the  tryptophane 
complex  in  the  protein  molecule  is  the  chief  precursor  of 
melanin  in  such  subjects. 

The  more  important  products  resulting  from  trypto- 
phane in  biological  processes  are  represented  by  the  fol- 
lowing transformations : 


Heterocyclic  Compounds 


399 


\ / 


CHAPTER   XXI 
THE   TERPENES 

228.  Many  of  the  volatile  oils  of  plants  are  esters,  but 
others  which  are  contained  especially  in  the  flowers  and 
stems  of  various  conif erae  consist  of  hydrocarbons  of  several 
types  and  their  derivatives.  These  are  grouped  together 
as  terpenes.  Turpentine  consists  of  'a  mixture  of  these, 
some  liquid  and  holding  in  solution  the  solid  forms.  On 
distilling  with  steam  the  lighter  members  pass  over,  and 
the  solid  residue  remaining  behind  is  colophony. 

Most  of  the  terpenes  correspond  to  the  formula  CioHi6. 
They  are  with  few  exceptions  unsaturated,  and  are  color- 
less, highly  refractive  liquids,  boiling  between  155  and  180°. 
Camphene  is,  however,  a  solid.  They  can  be  distilled  with 
steam  and  have  pleasant  odors.  They  are  soluble  in  many 
organic  solvents,  but  not  in  water.  The  terpenes  dissolve 
sulphur,  phosphorus,  iodine,  rubber,  and  resins,  and  are 
much  employed  as  solvents  in  varnishes,  paints  and  in  the 
arts.  In  most  cases  they  contain  one  or  more  asymmetric 
carbon  atoms  and  are  therefore  optically  active,  since, 
generally  speaking,  but  one  form  occurs  in  nature.  There 
are  a  few  instances  in  which  both  optical  forms  occur 
naturally.  They  are  easily  decomposed  by  acids. 

The  terpenes  yield  addition  products  with  nitrosyl 
chloride.  From  this  on  heating  with  alcoholic  potassium 

400 


The  Terpenes  401 

hydroxide  HC1  is  split  off,  leaving  a  nitroso  compound. 
They  add  on  ozone  at  the  points  of  double  linkage,  form- 
ing ozonides  of  the  general  type  : 


\CH  9^ 

II        +03=  >03 

CH  / 


The  ozonides  on  treatment  with  water  are  decomposed 
into  aldehydes : 

R\ 

NCHv  R— CHO 

-H20=  +H2Q, 

R— CHO 


The  terpenes  by  virtue  of  their  unsaturated  character 
form  addition  products  with  halogens.  On  reduction  they 
are  converted  into  hydroterpenes.  On  exposure  to  air 
they  are  oxidized  to  resins.  They  polymerize  also  to  form 
resins.  On  oxidation  with  potassium  permanganate 
they  are  in  many  cases  oxidized  to  benzene  derivatives. 
The  terpenes  may  be  considered  as  derived  from  hydro- 
carbons of  the  composition  C5H8,  of  which  isoprene  (82) 
is  an  example.  Two  or  more  molecules  of  this  substance 
can  polymerize  to  form  in  the  first  instance  a  hydrocarbon, 
CioHi6,  or  to  a  polyterpene,  (C5H8)n,  of  unknown  mole- 
cular weight.  The  compounds  of  this  series  found  in 
nature  warrant  the  classification : 
2D 


402     Organic  Chemistry  for  Students  of  Medicine 

1.  Hemiterpenes    C5H8        3.  Sesquiterpenes     Ci5H24 

2.  Terpenes  Ci0Hi6      4.  Diterpenes  C2oH32 

5.  Polyterpenes         (C5H8)n 

The  structure  of  many  natural  terpenes  has  been  deter- 
mined and  many  have  been  prepared  synthetically.  The 
formulae  assigned  to  a  few  of  those  possessing  open  and 
closed  chains  are  shown,  but  it  would  be  beyond  the  scope 
of  this  book  to  give  in  detail  the  methods  employed  in 
proving  their  structures : 


CH2  / 

>C— CH2— CH2— CH2— CH 


CH3 


XCH2—CH2OH 

Citronellol  (Lemon  oil) 


=:CH—  CH2—  CH2—  C 

CH—  CH2OH 

Geraniol  (Oil  of  geranium) 

CH.  /CH3 

\C=  CH—  CH2—  CH2—  C—  CH= 
CH/  \OH 


Linalool  (Oil  of  lavender) 


2—  CH2— 

H=CH2 

Myrcene 

Another  class  of  terpenes  are  derivatives  of  hydro  ben- 
zene. Thus  menthane  is  closely  related  to  cymene,  which 
is  a  constituent  of  many  volatile  oils  of  plants  : 


CH3 


The  Terpenes 
CH3 
CH 


403 


CH3 
CH 


HC      CH 
HC      CH" 

v 

C 

CH 
CH3  CH3 

Cymene 


+  4HH2C     CH2 


+  2H 


CH 


H2C 
'H,C 


CH2 


/\ 
CH3  CH3 

Menthene 


CH 

Menthane 


In  certain  cases  it  is  necessary,  in  order  to  account  for  all 
the  facts,  to  assign  still  more  complex  structures  to  individ- 
ual terpenes.  Thus  pinene,  Ci0Hi6,  is  believed  to  have 
the  structure : 


C 


H2C 


HC/ 


404     Organic  Chemistry  for  Students  of  Medicine 

CH 


CH3 

Borneol 

Assuming  the  skeleton  illustrated  and  a  union  between 
carbon  atoms  2  and  8,  pinene  consists  of  a  six-membered 
and  a  four-membered  ring.  Borneol  is  believed  to  have  a 
union  between  8  and  1,  giving  the  formula  shown  above. 

d-pinene  is  the  chief  constituent  of  turpentine  from 
America,  Algeria,  and  Greece,  while  that  from  France  and 
Spain  is  1-pinene.  d-borneol  is  found  in  the  product  from 
Borneo  and  Sumatra.  ! 

Camphor  is  a  sesquiterpene  from  the  camphor  tree.  It 
is  now  made  from  pinene  by  oxidation.  It  differs  from 
pinene  in  containing  a  ketone  group. 

229.  The  Cholesterols  are  closely  related  to  the  ter- 
penes.  While  they  resemble  the  hard  fats  in  their  phys- 
ical properties,  they  differ  from  these  in  their  remarkable 
stability  toward  oxidation.  Micro-organisms  do  not 
attack  them  and  they  appear  to  be  formed  in  every  cell 
for  protective  purposes,  and  they  play  an  important  role 
in  the  living  protoplasm  by  reason  of  their  peculiar  physi- 


The  Terpenes  405 

cal  properties.  The  structure  of  cholesterol  is  not  entirely 
known,  but  Windaus  assigns  to  it  the  following  partial 
provisional  constitution  : 


CH3 

CH    CH 


H2C      CH   CH— 

I        I         I 

.H^O  OxT-2     C'-H. 

\/         '      II 

CHOH  CH2 

The  nature  of  the  complex  CuHn  is  entirely  unknown. 
The  properties  of  cholesterol  have  already  been  described 
(99). 


CHAPTER  XXII 
THE    ALKALOIDS 

The  term  alkaloid  now  includes  those  basic  substances 
occurring  in  plants  which  are  derived  from  pyridine, 
quinoline,  isoquinoline,  tropaine,  or  pyrrolidine. 

230.  Pipeline,  CnHigNOs,  is  a  derivative  of  pyridine. 
On  hydrolysis  it  yields  piperidine  and  an  acid,  piperic  acid, 
which  may  be  regarded  as  the  methylene  ester  of  cinna- 
menylacrylic  acid : 


A 

/       \ 

—  CH  =  CH—  CH  =  CH—  C 

CH2 

\J 

| 

\/ 

I     I                   1 

N 


Methylene  cinnamenyl  group         Acrylic  acid  group          , 

CH2 

Piperidine 

Piperine  is  a  white  solid  substance  melting  at  128°.  It 
does  not  dissolve  in  water,  but  is  soluble  in  alcohol  and 
ether.  Black  pepper  contains  about  8  per  cent  of  this 
alkaloid. 

231.  Coniine,  C8Hi7N,  is  the  poisonous  principle  of 
the  hemlock.  It  is  dextrorotatory  a-n-propylpiperidine. 
It  is  a  strong  base  which  distills  with  steam  when  the  seeds 

406 


The  Alkaloids  407 

of  hemlock  are  distilled  with  sodium  hydroxide.  It  was 
the  first  of  the  alkaloids  to  be  synthesized.  The  steps 
by  which  Ladenburg  accomplished  this  are  as  follows : 

CH3I   I        i  Heat 

r  — CH3 

N  N  N 

e  /\  a-methyl  pyrid 

/       \  (o-picolme) 

/~«TT         T 

v^-tla     1 


(acetaldehyde) 

N 
CH2 


H2C      CH— CH2-CH2— CH3 

v 

N 

a-propyl-piperidine  (coniine) 

232.   Nicotine,  Ci0Hi4N3,  contains  both  a  piperidine  and 
a  pyrrolidine  ring.     It  is  a  colorless  oily  substance  which 
CH2       H2C  —  CH2 

/\       I    I 

H2C     CH CH   CH2 

I    I       v 

H2C      CH2          N 

\S  I 

NH  CH, 


408    Organic  Chemistry  for  Students  of  Medicine 

boils  at  247°  and  has  an  unpleasant  smell  and  an  ex- 
tremely burning  taste.  Naturally  occurring  nicotine  is 
levorotatory.  The  synthetic  product  is  inactive,  and 
d-nicotine  has  been  prepared  from  it  and  from  the  natural 
product  after  racemization.  The  physiological  effects  of 
the  natural  form  are  twice  as  pronounced  as  are  those  of 
the  optical  isomer  d-nicotine.  It  is  extremely  poisonous. 

The  alkaloids  are  not  found  generally  distributed  in 
plants,  but  certain  ones  are  produced  only  by  particular 
plant  groups.  The  formation  of  pyrrolidine  from  tetra- 
methylene  diamine  (117)  and  piperidine  from  pentamethyl- 
ene  diamine  (320)  give  a  clue  to  their  mode  of  formation 
in  the  metabolism  of  the  plant.  These  are  formed  from 
ornithine  and  lysine  respectively,  both  of  which  amino 
acids  occur  in  the  course  of  protein  decomposition.  The 
formation  of  alkaloids  is  doubtless  closely  associated  with 
the  protein  metabolism  of  the  plant. 

233.  Hygrine,  an  alkaloid  found  in  coca  leaves,  is 
/3-acetyl-N-methyI  pyrrolidine : 

H2C— CH— CO— CHs 


Y  :  ; 

H, 

234.  Atropine  and  Hyoscyamine  differ  chemically  only 
in  respect  to  their  optical  properties,  the  former  being 
the  d,  1-  and  the  latter  the  1-hyoscyamine.  Atropine  is 
found  in  the  deadly  nightshade  and  in  henbane,  and 


The  Alkaloids 


409 


hyoscyamine  in  the  Jamestown  weed,  Datura  stramonium. 
It  is  a  white  crystalline  substance  melting  at  115°, 
readily  soluble  in  alcohol,  ether,  and  chloroform,  but 
sparingly  soluble  in  water.  It  is  one  of  the  most  poisonous 
substances  known. 

On  hydrolysis  atropine  yields  tropic  acid  and  tropine. 
Tropic  acid  has  been  shown  to  be  o-phenyl-^-hydroxy 
propionic  acid : 


CH— C6H5 

COOH 

Tropine  is  made  up  of  two  condensed  rings,  one  with 
five  members,  the  other  with  six,  a  nitrogen  atom  serving  as 
a  "  bridge." 

H2C CH CH2 


N— CH3     CHOH 


H2C- 


J.-L 

Tropine 

H2( 
n«,r 

""                 TTT 

PTT      prvyfT 

N—  CH3 

PTT 

L/±l      l^UUxl 

CHOH 
ru- 

Ecgonine 

Atropine  is  the  ester  of  tropic  acid  with  the  secondary 
alcohol  tropine. 

235.  Cocaine,  Ci7H2iNO4,  is  an  alkaloid  in  coca  leaves. 
It  is  crystalline  and  melts  at  98°.  On  hydrolysis  it  yields 
methyl  alcohol,  benzoic  acid,  and  ecgonine.  Its  formula  is : 


410     Organic  Chemistry  for  Students  of  Medicine 
H2C  -  CH  -  HC—  COOCH3 

! 

CH-OOC-C6H6 


236.  Cinchonine,  Ciglfe^O,  present  with  quinine  in 
cinchona   bark,  yields   cinchonic  acid  or  quinoline  car- 
boxylic  acid  and  a  piperidine  derivative. 

The  structure  of  quinine  is  similar  but  is  not  known  with 
certainty.  It  yields  both  quinoline  and  pyridine  deriva- 
tives on  hydrolysis. 

237.  Strychnine,  C2iH22N2O2  ;  Brucine,  C23H26N2O4,  and 
Curarine  are  all  present  in  the  seeds  of  Strychnos  nux 
vomica  and  other  plants  of  that  family.      They  are  all 
extremely  poisonous.     Strychnine  yields  both  quinoline 
and  indol   on  fusion  with  alkalies.     The  constitution  of 
these  alkaloids  is  not  known. 

238.  Morphine,  Ci7Hi9NO3,  occurs  in  the  juice  of  the 
poppy.    There  are  a  number  of  other  alkaloids  in  the  plant. 
Opium  is  the  dried  juice  of  the  seed  capsule  of  Papaver 
somniferum,  a  variety  of  poppy.      It  contains  other  alka- 
loids as  well  as  a  large  number  of  substances  such  as  fats, 
resins,  proteins,  sugars,  inorganic  salts,  etc. 

239.  Papaverine,   Narcotine,   Narceine,   Laudanosine, 
are  all  found  in  opium  along  with  morphine.    They  are 
derivatives  of  isoquinoline. 


CHAPTER  XXIII 
ORGANIC   ARSENIC   COMPOUNDS 

240.  Cacodylic  acid,  (CH3)2AsO— OH.  This  organic 
arsenic  derivative  is  formed  when  potassium  acetate  is 
distilled  with  arsenic  trioxide.  The  principal  reaction  is 
represented  by  the  following  equation: 

As2O34-4CH3— COOK 

=  (CH3)2=As— O— As=(CH3)2  +  2  K2CO3  +  2  CO2 

Cacodyl  oxide 

The  distillate  is  an  oily  liquid  with  an  overpowering 
odor  and  extremely  poisonous  properties.  The  radical 
— As(CH3)2  corresponds  to  — N(CH3)2.  In  the  distillate 
is  also  a  substance  called  cacodyl : 

(CH3)2=As— As=(CH3)2 

Cacodyl 

Cacodyl  and  its  homologues  are  analogous  to  the  sub- 
stituted hydrazines  R2=N — N=R2. 

Cacodyl  oxide  when  treated  with  hydrochloric  acid 
yields  cacodyl  chloride : 

(CH3)2=As— O— As=(CH3)2  +  HC1  =2(CH3)2As— Cl 
Both  cacodyl  and  cacodyl  oxide  are  converted  into  caco- 
dylic  acid  by  oxidation.     The  most  important  salt  is  the 
sodium  salt,  which  has  been  much  used  in  medicine.     It 
corresponds  to  the  formula 

(CH3)2AsO— ONa  +3  H2O 
411 


412     Organic  Chemistry  for  Students  of  Medicine 

This  salt  is  a  white  crystalline  powder  which  dissolves 
readily  in  water.  It  is  much  less  poisonous  than  are  the 
salts  of  arsenious  acid. 

241.  Arrhenal,  sodium  methyl  arsenate, 

CH3—  AsO(ONa)2, 

is  formed  by  the  action  of  methyl  iodide  on  sodium  arsenate 
in  alkaline  solution  : 

/ONa  /CH3 

O  =  As^-ONa  +  CH3I  =  O  =  As—  ONa  +  NalO 
\ONa  \ONa 

The  great  stability  of  these  arsenic  derivatives  containing 
aliphatic  radicals,  and  the  correspondingly  slight  arsenical 
effect  which  follows  their  administration,  has  led  to  the 
substitution  in  great  measure  of  aromatic  arsenic  com- 
pounds in  medicine. 

242.  Atoxyl,  sodium  p-amino-phenyl-ar  senate,  is  formed 
when  aniline  and  arsenic  acid  are  heated  together.     As  an 
intermediate  product,  aniline  arsenate,  is  formed  : 

/OH 
C6H5NH2  +  As(OH)3  =  C6H5NH3—  OAs^ 

Anilin  arsenate 


/OH 

NH2—  C6H4As==O 
\OH 

p-amino-phenyl-arsenic  acid 

/ONa 

Acetylatoxyl,  CH3—  CO—  NH—  C6H4—  As=O     ,  is  also 

\OH 

Acetyl  atoxyl 

employed   as  a  compound  for  the   slow  administration 
of  arsenic  in  medicine. 


Organic  Arsenic  Compounds 


413 


Salvarsan,  an  arsenic  compound  having  a  peculiar 
specific  toxic  effect  upon  the  protozoa  causing  syphilis,  is 
one  of  the  most  valuble  remedies  yet  discovered.  It  is 
p-dihydroxy-m-diamino-arseno-benzene.  The  following 
reactions  illustrate  its  preparation  : 

NH2  NH2 

N. 

'As  =  As 

p-dihydroxy-m-diamino-arseno-benzene 

On  heating  phenol  with  arsenic  acid,  condensation  takes 
place  at  the  para  position : 


H  +  HO— As=O 

\)H 

OH 

i=O  +H2O 
\)H 

p-phenol  arsenic  acid 

On  nitration  this  yields  a  nitro  derivative  having  the 
— NO2  group  in  the  o-  position  to  the  — OH.  On 
complete  reduction  of  this  compound  the  nitro  group  is 
converted  into  an  amino  group  and  the  oxygen  is  removed 
from  the  arsenic  acid  group,  the  two  residues  are  condensed  : 

NO2  /OH 

2  HO/        \As=0   +20H 

\)H 
NH2  NH2 


=  HO 


H  +  10H2O 


414     Organic  Chemistry  for  Students  of  Medicine 

Salvarsan  is  a  derivative  of  arseno-benzene, 

C6H6— As  =  As— C6H5 
which  is  analogous  to  azo  benzene :  C6H5 — N  =  N — C6H6. 

THE   PROTEINS 

243.  The  proteins  form  a  very  important  group  of  sub- 
stances which  constitute  the  greater  part  of  the  solids  of 
animal  tissues  and  are  present  in  all  tissues  of  both  animal 
and  plant  origin.  Typical  proteins  are  the  white  of  egg, 
casein  of  milk,  which  is  the  part  separated  in  the  curdling 
of  milk,  hair,  nails,  silk,  etc. 

Chemically  the  proteins  are  made  up  of  amino  acids ; 
seventeen  of  these,  glycocoll,  alanine,  valine,  leucine  and 
isoleucine,  phenylalanine,  tyrosine,  serine,  cystine,  pro- 
line,  oxyproline,  aspartic  acid,  glutaminic  acid,  arginine, 
lysine,  histidine,  and  tryptophane  have  been  isolated  and 
identified.  These  have  all  been  described  in  this  book. 
It  is  possible  that  there  are  others  as  yet  unidentified. 

The  proteins  differ  most  widely  in  their  physical 
properties,  some  being  soluble  in  water  (albumins),  others 
insoluble  in  water,  but  soluble  in  dilute  salt  solutions 
(globulins),  others  insoluble  in  both  these  solvents,  but 
soluble  in  dilute  acids  or  alkalies  (glutelins).  There  is  a 
class  called  prolamines,  which  are  especially  abundant  in 
wheat,  rye,  barley,  and  maize,  which  are  insoluble  in 
water  or  salt  solutions,  but  dissolve  readily  in  70-80  per 
cent  alcohol. 

Nearly  all  proteins  contain  sulphur,  and  a  few  also  contain 
phosphorus;  the  latter  occur  only  in  milk  and  in  eggs. 


The  Proteins  415 

Simple  proteins  on  hydrolysis  with  mineral  acids  yield 
only  a-amino  acids.  The  structure  of  the  proteins  has  been 
made  clear  by  the  work  of  E.  Fischer,  who  has  produced 
numerous  synthetic  products  closely  similar  to  the  natural. 

The  proteins  consist  of  amino  acids  in  "  peptide  "  union 
with  each  other.  This  union  results  from  the  interaction 
of  the  carboxyl  group  of  one  with  the  a-amino  group  of 
another : 


— C0|  OH     +  H  |HN— CH2— COOH 

Glycine  (glycocoll) 

NH2  =  CH3— CH— CO— NH— CH2— COOH 

Alanine  I 


NH2 

Alanyl-glycine 

CH3—  CH—  CO—  NH—  CH2—  CO 
NH2 

OH         CH2—  C6H6 
H[HN—  CH 

COOH 

Phenylalanine 

CH2 


=  CH3— CH— CO— NH— CH2— CO— NH 

NH2  COOH 

Alanyl-glycyl  phenylalanine 

Such  complexes  are  called  di-,  tri-,  tetra-,  etc.  peptides  ac- 
cording to  the  number  of  amino  acid  molecules  which  they 
contain.  The  number  of  compounds  which  it  is  possible 
to  form  from  seventeen  amino  acids  arranged  in  different 
orders  is  extremely  great  and  readily  accounts  for  the  very 
numerous  proteins  found  in  the  plant  and  animal  world. 


416    Organic  Chemistry  for  Students  of  Medicine 

Proteins  are  known  which  consist  of  the  three  diamino 
acids  arginine,  lysine,  and  histidine,  and  arginine  in  one 
instance  constitutes  about  85  per  cent  of  the  total  nitro- 
gen content.  These  are  termed  protamines  and  occur 
only  in  the  heads  of  the  spermatozoa  of  animals. 

Proteins  differ  greatly  in  the  proportions  of  the  different 
amino  acids  which  they  yield.  Glutamic  acid  occurs  to 
the  extent  of  40  per  cent  in  certain  of  the  wheat  proteins 
(gliadin)  and  as  little  as  2  per  cent  in  the  globulin  globin 
of  the  blood.  Silk  is  more  than  half  made  up  of  peptide 
combinations  of  glycocoll  and  alanine.  Tryptophane, 
tyrosine,  and  cystine  are  all  lacking  from  gelatin,  derived 
by  the  incipient  hydrolysis  of  connective  tissue,  the 
organic  matrix  of  bones,  etc.  A  few  yield  no  glycocoll. 

In  digestion  by  enzymes  such  as  pepsin  or  trypsin  the 
peptide  linkages  are  broken,  the  elements  of  water  being 
taken  up  to  form  an  amino  and  a  carboxyl  group,  i.e. 
digestion  is  the  reverse  of  the  process  described  in  the  for- 
mation of  the  peptides. 

THE    CONJUGATED   PROTEINS 

The  proteins  also  exist  in  nature  in  certain  instances 
in  union  with  other  substances  as  phosphoric  acid  (phos- 
phoproteins),  glucosamine  (glycoproteins),  nucleic  acids 
(nucleoproteins),  etc. 

The  chemistry  of  the  proteins  is  so  extensive  and  involves 
a  consideration  of  their  physical  properties  as  colloids,  as 
well  as  their  chemical  constitution,  that  it  properly  belongs 
in  the  special  branch  of  physiological  chemistry  and  will 
not  be  further  dealt  with  here. 


INDEX 


Absolute  alcohol,  25. 
Acetal,  59. 

Acetaldehyde,  53,  65. 
Acetaldoxime,  63,  72,  88. 
Acetamide,  104. 
Acetanilide,  361. 
Acetate,  ethyl,  103. 
Acetic  acid,  53,  71,  77,  99,  101 

anhydride,  126. 

ester,  103. 
Aceto-acetic  acid,  236,  237. 

ester,  238-241. 
Acetone,  68,  69,  73,  102,  236. 

dicarboxylic  acid,  244. 
Aceto  nitrile,  78. 
Acetoxime,  72. 
Acetylation,  103,  188. 
Acetyl  chloride,  95. 

number,  188. 

urea,  253. 

Acetylene,  163,  166,  347. 
Acetylenes,  161,  162. 
Achroodextrine,  330. 
Acid  amides,  104. 

anhydrides,  126. 

chlorides,  95,  103. 

number,  183. 

ureides,  260. 

Acids,  amino,   120,   137,   139, 
206,  208,  368,  398. 

dibasic,  199. 

fatty,  95-151. , 

monobasic,  95. 
Acrolein,  168,  289. 
Acrose,  290. 
Acrylic  acid,  173,  407. 
Acylation,  122,  127. 
Addition  compounds,  58. 
Adenase,  279. 
Adenine,  278. 


Adipic  acid,  208,  212. 

Adonite,  296. 

Adrenin,  376. 

^Etioporphyrin,  221. 

Alanine,  137,  415. 

Alanyl-glycine,  415. 

Alanyl-glycyl-phenylalanine,  415 

Albumins,  414. 

Alcohol,  24, 106,  201,  340. 

Alcoholates,  26. 

Alcoholic  fermentation,  338. 

Alcohols,  22. 

Aldehyde,  53. 

ammonia,  58,  66. 
Aldehydes,  53,  56. 

aromatic,  354,  379. 
Aldol,  61. 

condensation,  61. 
Aldose,  284. 
Aldoximes,  63,  72. 
Aliphatic  series,  1—21. 
Alizerin,  386,  387. 
Alkaloids,  406. 
Alkaptonuria,  376. 
Alkyl  ammonias,  85,  90. 

anilines,  361. 

cyanates,  112. 

cyanides,  77,  78. 
147,        halides,  12. 

isocyanates,  80,  81. 

isocyanides,  79,  80. 

thiocyanates,  80,  81. 
Allantoine,  256. 
Allene,  161. 
Alloxan,  261,  262. 
Alloxantine,  263. 
Allyl  alcohol,  167. 

isothiocyanate,  169. 

pyridine,  407. 

sulphide,  169. 
417 


418 


Index 


Aluminum  carbide,  166. 
Amides,  98,  104. 
Amines,  84,  87,  94. 
Aminoacetic  acid,  120. 
a-Amino  acids,  109. 
/3-Amino  acids,  169. 
7-Amino  acids,  237. 
Amino  benzene,  359. 

glucose,  334. 

glutaric  acid,  208. 

isocaproic  acid,  147. 

isovalerianic  acid,  143. 

naphthalene,  384. 

nitrogen,  121. 

oxypurine,  278. 

propionic  acid,  137,  415. 

purine,  278. 
Ammonium  carbamate,  110. 

formate,  77. 

isocyanate,  111. 

thiocyanate,  115. 

urate,  272. 
Amygdalin,  324. 
Amyl  alcohols,  30. 

nitrate,  48.  » 

nitrite,  48. 
Amylase,  329. 
Amylum,  329. 
Anhydrides,  acid,  126. 
Aniline,  359,  361. 
Anthracene,  385. 
Anthraquinone,  386. 
Antipyrine,  259. 
Araban,  332. 
Arabinose,  296. 
Arabite,  296. 
Arachic  acid,  151. 
Arginine,  118. 
Argol,  231. 

Aromatic  compounds,  346. 
Arrhenal,  412. 

Arsenic,  compounds,  organic,  411. 
Asparagine,  207. 
Aspartic  acid,  206. 
Aspirin,  381. 

Asymmetric  carbon  atom,  34,  206. 
Atoxyl,  412. 
Atropine,  408. 
Azeliac  acid,  173,  213. 


Azo  benzene,  414. 
dyes,  390. 

Barbituric  acid,  261. 
Beeswax,  192. 
Behenic  acid,  151. 
Benzal  chloride,  355,  377. 
Benzaldehyde,  354,  379. 
Benzene,  347,  352,  363. 

sulphonic  acid,  364. 

sulphonyl  chloride,  364. 
Benzoic  acid,  354,  377. 
Benzoin,  380. 
Benzo  nitrile,  363. 

trichloride,  355,  377. 
Benzoyl  glycine,  378. 
Benzyl  alcohol,  377,  379. 

chloride,  355,  377. 
Betaine,  125. 
Betaines,  125. 
Beverages,  alcoholic,  27. 
Biuret,  112. 
Bone  oil,  392. 
Borneol,  403. 
Brilliant  green,  388. 
Brom  benzene,  363. 
Brucine,  410. 
Burning  point,  15. 
Butane,  13,  18. 
Butter  fat,  176. 
Butyl  alcohols,  28. 
Butylenes,  162. 
Butyric  acids,  140. 

fermentation,  342. 
Butyro  betaine,  125. 

Cacodyl  compounds,  411. 
Cadaverine,  147. 
Caffeine,  281. 
Calcium  carbide,  165. 
Camphor,  403. 
Cane  sugar,  318,  328. 
Cannizarro  reaction,  61. 
Capric  acid,  151,  240. 
Caproic  acid,  146,  151,  345. 
Caprylic  acid,  151. 
Caramel,  319. 
Carbamic  acid,  110,  255. 
esters,  116. 


Index 


419 


Carbamide,  111,  113. 
Carbides,  165. 
Carbinol,  23,  57. 
Carbohydrates,  283-337. 

action  of  enzymes  on,  319-329. 

fermentation,  338-342. 

in  nucleic  acids,  301. 

in  proteins,  334. 
Carbolic  acid,  365. 
Carbon  atom,  asymmetric,  31-35. 

monoxide,  97,  98. 

tetrachloride,  9. 
Carbonyl,  57. 

chloride,  9. 
Carboxylase,  341. 
Carboxyl  group,  57. 
Carbylamine  reaction,  89. 
Carnauba  wax,  191. 
Carnaubyl  alcohol,  36. 
Carvicrol,  374. 
Casein,  414. 
Castor  oil,  177. 
Catalytic  action,  55. 
Catechol,  376. 
Cellulose,  330. 

acetates,  331. 

Centric  formula  of  benzene,  349. 
Cerebrosides,  197. 
Cerotic  acid,  151. 
Ceryl  alcohol,  36,  191. 
Cetyl  alcohol,  36. 
Chinese  wax,  191. 
Chinovose,  303. 
Chitin,  334. 
Chitosan,  334. 
Chitose,  336. 

Chloracetic  acids,  107,  205. 
Chloral,  60,  66. 

hydrate,  60,  67. 
Chlor  benzenes,  358. 
Chlorhydrins,  39,  41. 
Chloroform,  9. 
Chlorophyll,  222. 
Chlor  propionic  acid,  137. 
Chlortoluenes,  365. 
Cholesterols,  404. 
Choline,  92,  125,  196. 
Cinchonine,  410. 
Cinuamic  acid,  381. 


Cis  form,  171. 
Citric  acid,  245. 
Citronellol,  402. 
Coal  gas,  1. 

tar,  352. 
Cocaine,  409. 
Cocoa  butter,  176. 
Collidines,  393. 
Collodion,  331. 
Colophony,  400. 

Color  reactions  of  proteins,  368,  398. 
Congo  red,  390. 
Coniferin,  375. 
Coniferyl  alcohol,  374. 
Coniine,  406. 
Conjugated  proteins,  416. 
Constitution  of  proteins,  415. 
Coprosterol,  198. 
Cordite,  40. 
Cream  of  tartar,  231. 
Creatine,  123. 
Creatinine,  124. 
Cresols,  367. 

Crotonic  acids,  169,  173,  236. 
Croton  oil,  177. 
Cyanamide,  83,  116,  118. 
Cyanates,  82,  112. 
Cyanides,  78,  79. 

alkyl,  78. 

Cyano  benzene,  363. 
Cyanogen,  199. 
Cyanuric  acid,  113. 
Cyclohexane,  211. 
Cymene,  357. 
Cystine,  139. 
Cytosine,  264,  265. 

Deamination  of  amino  acids,  121, 

370,  399. 

Denatured  alcohol,  26. 
Desaturation  of  fats,  172. 
Dextrins,  330. 
Dextrose,  304. 
Diacetyl  urea,  253. 
Dialuric  acid,  261. 
Diamines,  147,  408. 
Diamino  acids,  118,  125,  146,  257. 

caproic  acid,  147. 

valerianic  acid,  29,  143. 


420 


Index 


Diastase  (see  amylase). 
Diatomic  alcohols,  37. 
Diazo  benzene,  362. 

reaction,  362. 
Diazonium  salts,  363. 
Dibasic  acids,  199. 

acid  ureides,  259. 
Dichlor  acetic  acid,  107. 

hydrin,  41. 
Diethyl  aniline,  361. 

arsine,  11. 

sulphite,  47. 
Digallic  acid,  382. 
Digitalin,  323. 
Dihydroxy  acetic  acid,  256. 

acetone,  75,  340. 

benzenes,  371. 

succinic  acid,  227,  249. 
Dimethyl  amine,  85,  91. 

aniline,  361. 

benzenes,  352,  356. 

selenide,  11. 

sulphate,  44. 

telluride,  11. 

xanthine,  281. 
Diolefines,  161. 
Diose,  294. 
Dioxypurine,  277. 
Dipeptides,  415. 
Diphenyl  amine,  361. 

methane,  357. 
Disaccharides,  318. 

hydrolysis  by  enzymes,  319,  321, 
Diterpenes,  402. 
Dodecyl  alcohol,  36. 
Double  bond,  154,  169,  172. 
Dry  distillation  of  wood,  100. 
Drying  oils,  176. 
Dulcite,  303. 
Dyes,  387-390. 

Ecgonine,  409. 
Egg  albumen,  414. 
Elaidic  acid,  172. 
Elaidin  test,  189. 
Empirical  formula,  8. 
Emulsin,  324. 
Emulsions,  182. 
Enantiomorphs,  134. 


Enol  form,  241. 
Enzymes,  338,  341. 
Eosin,  390. 
Erythrite,  42,  294. 
Erythrodextrine,  330. 
Erythrose,  294. 
Esters,  44. 
Ethanal,  65. 
Ethane,  10. 
Ethanol,  24. 
Ethers,  44,  48. 
Ethyl  acetate,  103. 

alcohol,  24. 

amine,  78,  79,  85,  91. 

carbinol,  24. 

chloride,  12,  13. 

ether,  48. 

mercaptan,  43. 

nitrate,  48. 

nitrite,  47. 

radical,  12. 

sulphates,  44,  49. 

sulphuric  acid,  44,  45. 

sulphurous  acid,  47. 
Ethylate,  sodium,  26. 
Ethylene,  154. 

chloride,  14,  247. 

cyanide,  205. 

dibromide,  158,  163. 

glycol,  37. 

oxide,  38. 
Ethylidene  chloride,  14. 

cyanhydrin,  58. 

glycol,  59. 

Fats,  175,  178. 

emulsification  of,  182. 

saponification  of,  179. 
Fatty  acids,  95-151,  343. 
Fehling's  solution,  58. 
Fermentation,  338-342. 
Fittig's  reaction,  11. 
Flash  point,  15. 
Fluorescene,  390. 
Formaldehyde,  54,  63. 
Formalin,  63. 
Form  amide,  98. 
Formic  acid,  61,  71,  77,  96. 

nitrile,  77. 


Index 


421 


Formol  titration,  88. 
Formose,  64,  289. 
Formula,  empirical,  8. 

general,  14. 

graphic,  6,  8. 

Friedal  and  Crafts  reaction,  353. 
Fructosazine,  268. 
Fructose,  307. 
Fruit  sugar,  307. 
Fucose,  303. 
Fulminic  acid,  82. 
Fumaric  acid,  247-252. 
Furfural,  292. 
Furfurane,  293. 
Fusel  on,  29,  31,  145. 

Galactan,  317,  332. 
Galactose,  306,  317. 
Gallic,  acid,  382. 
Gelatin,  416. 
Geraniol,  402. 
Glacial  acetic  acid,  102. 
Gliadin,  416. 
Globulins,  414. 
Gluconic  acid,  313. 
Glucosamine,  334,  416. 
Glucosan,  313. 
Glucose,  304,  312. 
Glucosides,  323,  324. 
Glutamic  acid,  208. 
Glutamine,  208. 
Glutaric  acid,  207. 

anhydride,  215. 
Glutarimide,  216. 
Glyceraldehyde,  68,  288,  340. 
Glyceric  acid,  230. 
Glycerides,  175. 
Glycerol,  39,  288. 
Glycero-phosphoric  acid,  193. 
Glycerose,  294. 
Glyceryl  esters,  175. 
Glycine,  120. 
Glycocoll,  120. 
Glycogen,  333. 
Glycol,  37,  106,  109,  201. 

aldehyde,  67,  106,  109. 

chlorhydrin,  39. 
Glycolic  acid,  108,  225,  254. 

ureides,  254. 


Glycolide,  225. 
Glycoluric  acid,  254. 
Glycuronic  acid,  313. 
Glyoxal,  68,  285. 
Glyoxaline  derivatives,  256. 
Glyoxylic  acid,  109. 
Granulose,  329. 
Grape  sugar,  312. 
Gualtherin,  324. 
Guanase,  280. 
Guanidine,  117. 
Guanine,  278. 
Guiachol,  371. 
Gums,  333. 
Guncotton,  331. 

Hsematin,  219. 
Hsemin,  220. 
Haemoglobin,  220. 
Haemoporphyrin,  221. 
Halogen  derivatives  of  fatty  acids, 
107. 

derivatives  of   hydrocarbons,    3, 

12,  13,  358. 
Hedonal,  117. 
Helianthin,  390. 
Hemicellulose,  332. 
Hemiterpenes,  402. 
Heptadecane,  16. 
Heptamethylene,  213. 
Heptanes,  16. 
Heptyl  alcohol,  36. 
Heterocyclic  compounds,  391. 
Hexabromide  test,  189. 
Hexahydric  alcohols,  295. 
Hexahydro  benzene,  347. 
Hexamethylene,  213,  347. 

tetramene,  63. 
Hexane,  16. 

Hexoses,  295,  296,  303,  311. 
Hexyl  alcohol,  36. 

iodide,  287. 
Hippuric  acid,  378. 
Histamine,  257. 
Histidine,  125,  257. 
Homogentisic  acid,  375. 
Homologous  series,  12. 
Hormones,  376. 
Hydantoic  acid,  255. 


422 


Index 


Hydantoin,  254,  255. 

Hydrazine,  62. 

Hydrazones,  72,  285. 

Hydro  aromatic  compounds,  347. 

Hydrocarbons,  1,  154,  163,  347. 

saturated,  1-21. 

unsaturated,  154,  163. 
Hydrocyanic  acid,  77,  199. 
Hydroquinone,  372. 
Hydroxy  acids,  108. 

aldehydes,  67,  109. 

benzoic  acid,  381. 

butyric  acid,  169,  235. 
Hydroxyl  group,  220,  383. 
Hydroxyphenyl  acetic  acid,  370. 

alanine,  368. 

ethyl  amine,  370. 

propionic  acid,  370. 
Hydroxy proline,  224. 
Hydroxypropionic  acid,  129. 
Hygrine,  408. 
Hyoscyamine,  408. 
Hypoxanthine,  277. 

Idose,  306. 
Imidazoles,  257. 

acrylic  acid,  257. 

amino-propionic  acid,  125,  257. 

ethyl  amine,  257. 
Imides,  216. 
Imino  group,  216. 
Inactive  tartaric  acid,  229,  232. 
India  rubber,  161. 
Indican,  397,  399. 
Indigo,  397. 

white,  397. 
Indole,  395,  399. 

acetic  acid,  399. 

amino-propionic  acid,  399. 

ethyl  amine,  399. 

propionic  acid,  399. 
Indoxyl,  396,  399. 
Ink,  382. 
Inosite,  373. 

Internal  compensation,  229,  297. 
Inulin,  336. 
Inversion,  319. 
Invertase,  319. 
Invert  sugar,  319. 


Iodine  number,  186. 
lodobenzene,  359,  363. 
lodoform,  74. 
Isoamylamine,  92. 
I  so  butane,  18. 
Isobutyl  alcohol,  29,  145. 

amine,  92. 

Isobutyric  acid,  75,  141. 
Isocyanates,  alkyl,  80. 
Isocyanides,  alkyl,  78,  80. 
Isohcemopyrrol ,  219. 
Isoleucine,  149. 
Isomaltose,  320. 
Isomers,  19,  34. 
Isonicotinic  acid,  394. 
Isonitrile  reaction,  89. 
Isonitriles,  77,  78,  80. 
Isophonopyrrol     carboxylic      acid, 

219. 

Isophthalic  acid,  356. 
Isoprene,  161. 
Isopropyl  alcohol,  28,  70. 

iodide,  42. 
Isoquinoline,  394. 
Isothiocyanates,  alkyl,  80,  81. 
Isourea,  112. 
Isovalerianic  acid,  143. 

Japan  wax,  191. 

Keratins,  414. 
Kerosene,  15. 
Keto  acids,  236,  237,  242. 

form,  241. 
Ketones,  53,  68. 
Ketoses,  307. 
Kiliani's  reaction,  290. 
Kryptopyrrol,  219. 

Lactam,  237.  , 
Lactase,  321. 
Lactic  acid,  129,  340. 
fermentation,  342. 
Lactones,  237. 
Lactose,  318,  321. 
Lanolin,  192. 
Laurie  acid,  151. 
Lavender  oil,  402. 
Lecithins,  93,  193. 


Index 


423 


Leucine,  147. 
Levulinic  acid,  243. 
Levulose,  307. 
Lignin,  331. 
Ligroin,  15. 
Linoleic  acid,  174. 
Linolic  acid,  173. 
Lipase,  178,  180. 
Lutidines,  393. 
Lysine,  146. 
Lyxose,  296. 

Magenta,  389. 

Magnesium  in  chlorophyll,  222. 

Malachite  green,  388. 

Maleic  acid,  247-251. 

Malic  acid,  226,  249. 

Malonic  acid,  202. 

Malonic  ester  synthesis,  203. 

Malonyl  urea,  261. 

Maltose,  318,  320,  327. 

Mandelic  acid,  324,  380. 

Mannan,  312. 

Mannite,  312. 

Mannose,  312. 

Marsh  gas,  1,  2,  3,  6. 

Melibiose,  323. 

Melissic  acid,  151,  191. 

Melting  point,  183. 

Menthane,  403. 

Menthene,  403. 

Mercaptans,  42,  81. 

Mesitylene,  356. 

Mesotartaric  acid,  229,  232. 

Mesoxalic  acid,  242. 

Mesoxalyl  urea,  261. 

Meta  derivatives,  348. 

Metaldehyde,  66. 

Methane,  1. 

Methylal,  64. 

Methyl  alcohol,  22. 

amine,  85,  90. 

aniline,  361. 

benzene,  352,  354. 

chloride,  3. 

glucosides,  325. 

glyoxal,  340. 

guanidine  acetic  acid,  124. 

hnidazole,  315. 


iodide,  10. 

mercaptan,  43. 

methylene  amine,  88. 

nitrile,  77. 

nonyl-ketone,  240. 

pentose,  303. 

phenylhydrazine,  317. 

urea,  112. 
Methylene,  5,  9,  154. 

amino  acids,  122. 

chloride,  4,  9. 
Millon's  reaction,  369. 
Mixed  ethers,  52. 
Molasses,  318. 
Monochlorhydrin,  41. 
Morphine.  410. 
Mucic  acid,  235,  317. 
Mucilages,  333. 
Murexide  reaction,  263. 
Muscarine,  125,  196. 
Mustard  oil,  169. 
Myrcene,  402. 
Myricyl  alcohol,  36,  191. 
Myristic  acid,  151. 
Myrosin,  324. 
Myrtleberry  wax,  191. 

Naphtha,  15. 
Naphthalene,  384. 
Narcotine,  410. 
Neurine,  93,  195. 
Nicotine,  407. 
Nicotinic  acid,  393. 
Nitriles,  77. 
Nitrobenzene,  359. 
Nitrocellulose,  331. 
Nitroglycerine,  40. 
Nitroso  compounds,  393. 
Nonyl  alcohol,  36. 
Normal  carbon  chains,  18. 
Nucleic  acids,  301. 

Octadecyl  alcohol,  36. 
Octane,  16. 
Octyl  alcohol,  36. 
Oil,  olive,  176. 
Oils,  176. 

drying,  176. 
Olefines,  153. 


424 


Index 


Oleic  acid,  169,  172. 

Olein,  175. 

Optical  activity,  32. 

Orcin,  372. 

Ornithine,  119,  142. 

Ortho  derivatives,  348. 

Osazones,  285,  311. 

Osones,  311. 

Oxalacetic  acid,  243. 

Oxalic  acid,  106,  109,  199,  201,  202, 

nitrile,  199. 
Oxaluric  acid,  259. 
Oxalyl  urea,  260. 
Oximes,  63,  72. 
Oxy  acids,  129,  237. 
/3-Oxybutyric  acid,  169,  235. 
Oxydases,  54. 
Oxyethylamine,  92. 
Oxyphenylpropionic  acid,  370. 
Oxyproline,  224. 
Oxypurines,  274,  277. 
Ozonides,  401. 

Palmitic  acid,  151. 
Palmitin,  176. 
Papaverine,  410. 
Parabanic  acid,  259. 
Para  derivatives,  348. 
Paraffin,  16. 
Paraldehyde,  65. 
Pararosaniline,  388. 
Pectins,  333. 
Pelargonic  acid,  173. 
Pentamethylene,  211. 

diamine,  147,  408. 
Pentanes,  19,  32. 
Pentosans,  332. 
Pentose  in  nucleic  acids,  301. 
Pentoses,  295,  301. 
Peptides,  415. 
Petroleum,  15. 

benzine,  15. 

ether,  15. 

naphtha,  15. 
Phenates,  365. 
Phenol,  363,  365. 

ethers,  367. 

sulphonic  acid,  366. 
Phenolphthalein,  389. 


Phenyl  acetic  acid,  380. 

alanine,  380. 

amine,  360. 

cyanide,  363. 

hydrazine,  285. 

methane,  352,  354. 

propionic  acid,  380. 

radical,  360. 

sulphuric  acid,  366. 
Phlorizin,  323. 
Phloroglucinol,  373. 
Phosphatides,  193. 
Phospho-proteins,  416. 
Phthalic  acid,  356,  384. 

anhydride,  356. 
Phyllopyrrol,  219. 
Phytic  acid,  372. 
Phytosterols,  197. 
Picolines,  393. 
Picolinic  acid,  394. 
Picric  acid,  368. 
Pimelic  acid,  209,  213. 
Pinene,  403. 
Piperazine,  269,  270. 
Piperic  acid,  406. 
Piperidine,  391,  392,  393. 
Piperine,  406. 

Polymerization,  64,  65,  164. 
Polysaccharides,  329. 
Polyterpenes,  402. 
Primary  alcohols,  28. 

amines,  85. 
Proline,  223. 

betaine,  125. 
Propane,  13,  17. 
Propionic  acid,  71,  127,  204. 
Pro pio nitrile,  78. 
Propyl  alcohol,  28. 

chloride,  17. 
Propylene,  159. 

glycol,  39. 

Propylidene  chlorides,  160. 
Protamine,  416. 
Proteins,  414. 

conjugated,  416. 

Constitution,  415. 

hydrolysis,  416. 

putrefaction,  369. 
Protocatechuic  acid,  374. 


Index 


425 


Pseudo  urea,  112,  116. 

uric  acid,  272. 
Psylla  wax,  191. 
Purine,  275,  276. 
Purines,  270-282. 
Putrefaction,  369. 
Putrescine,  143. 
Pyrazines,  266. 
Pyrazole,  259. 
Pyridine,  392,  407. 
Pyrimidines,  264,  391. 
Pyrocatechin,  371. 
Pyrogallol,  373. 
Pyroligneous  acid,  100. 
Pyromucic  acid,  292. 
Pyroracemic  acid,  230. 
Pyrrol,  216,  389. 
Pyrrolidine,  216,  222. 

carboxylic  acid,  223. 
Pyrrolidone  carboxylic  acid,  224. 
Pyrroline,  216. 
Pyruvic  acid,  131,  230,  340,  344. 

Quaternary  amines,  86. 
Quinine,  410. 
Quinoline,  394. 
Quinolinic  acid,  394. 
Quinone,  372. 

Racemic  acid,  229,  232. 
Raffinose,  307,  323. 
Reichert-Meissl  number,  187. 
Resorcin,  390. 
Resorcinol,  372. 
Rhamnose,  303. 
Rhigoline,  15. 
Ribose,  296. 
Ricinoleic  acid,  177. 
Rochelle  salt,  231. 
Rosaniline,  389. 
Ruberythric  acid,  387. 

Saccharic  acid,  235,  304,  313. 
Saccharin,  378. 
Salicin,  323,  381. 
Salicylic  acid,  381. 

aldehyde,  381. 
Salol,  382. 
Salvarsan,  413. 


Sandmeyer  reaction,  364. 
Saponification,  179,  180. 

number,  183. 
Sarcolactic  acid,  133. 
Sarcosine,  124,  255. 
Scatole,  396,  399. 
Secondary  alcohols,  28. 
Serine,  140. 
Sesquiterpenes,  402. 
Side  chains,  350,  354. 
Silk,  416. 
Soaps,  179,  190. 
Sorbic  acid,  344. 
Sorensen  titration,  88,  122. 
Spermaceti,  192. 
Stachydrine,  125. 
Starch,  329. 
Stearic  acid,  151. 
Stearin,  175. 
Stereoisomerism,  34. 
Sterols,  197. 
Strychnine,  410. 
Suberic  acid,  209,  213. 
Succinic  acid,  205. 

anhydride,  215. 
Succinimide,  216. 
Sucrose,  318,  328. 
Sugars,  283-323. 
Sulphonal,  74. 
Sulphur  alcohols,  42,  81. 

Tannic  acid,  382. 
Tannins,  382. 
Tartar  emetic,  232. 
Tartaric  acid,  227,  249,  294. 
Tartronic  acid,  225,  294. 
Tartronyl  urea,  261. 
Tautomerism,  276. 
Teraphthalic  acid,  356. 
Terpenes,  400. 
Terpentine,  400. 
Tertiary  alcohols,  28,  31. 

amines,  210. 

Tetrahydroxy  dibasic  acids,  235* 
Tetramethylene,  211. 

diamine,  143. 
Tetramethyl  methane,  19. 
Tetroses,  294. 
Theobromine,  2S1. 


426 


Index 


Thio  alcohols,  42,  81. 
Thiocyanates,  alkyl,  80,  81. 
fhiourea,  115. 
Thymine,  264,  265. 
Thymol,  374. 
Toluene,  352,  354. 
Toluidines,  361,  389. 
Trans  form,  171. 
Tribrom  aniline,  360. 

phenol,  367. 
Trichlor  acetic  acid,  107. 

methane,  9. 
Trihydric  alcohols,  39. 

phenols,  373. 
Trihydroxy benzenes,  373. 
Trihydroxy  glutaric  acid,  235. 
Triiodo  propane,  39. 
Trimethyl  amine,  85. 
Trimethylene,  210. 
Triolein,  172. 
Trioses,  294. 
Trioxyglutaric  acid,  295. 
Trioxymethylene,  64. 
Trioxy  purine,  271,  274. 
Tripeptides,  415. 
Triphenylamine,  362. 
Triphenyl  methane,  357,  388. 
Triple  bond,  163. 
Trisaccharides,  307,  323. 
Tropic  acid,  409. 
Tropine,  409. 
Tryptophane,  398. 
Timicin,  331. 
Turpentine,  400. 
Tyramine,  370. 
Tyrosine,  368,  375. 

Unsaponifiable  residue,  184. 
Unsaturated  acids,  169,  172,  173. 

aldehydes,  168. 

hydrocarbons,  153,  161. 


Uracil,  264,  266. 
Uramil,  263,  272. 
Urea,  111,  113. 
Urease,  115. 
Ureides,  253-263. 
Urethane,  117. 
Uric  acid,  271,  274. 
Urocanic  acid,  257. 
Urotropin,  63. 

Valerianic  acid,  142. 
Valine,  29,  143. 
Vanillin,  374. 
Van  Slyke  reaction,  90. 
Varatric  acid,  374. 
Vaseline,  16. 
Veratrol,  371. 
Veronal,  261. 
Vinegar,  53. 
Vinyl  alcohol,  167. 

bromide,  159. 
Volatile  fatty  acids,  176,  177,  187. 

Walden's  transformation,  138. 
Waxes,  190. 
Wohl's  reaction,  290. 
Wood  alcohol,  22. 
distillation,  100. 
Wool  wax,  192. 

Xanthine,  277. 
oxidase,  280. 
Xylan,  332. 
Xylenes,  352,  356. 
Xylite,  296. 
Xylose,  296.    , 

Yeast,  24,  340. 
Zinc  methyl,  10. 


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